Package 'nlmixr2autoinit'

Description

Estimates the volume of distribution (Vd) from observed peak concentrations (Cmax) in single-dose, multiple-dose, or mixed datasets.

Usage

approx.vc(
  dat = NULL,
  half_life = NULL,
  single_point_base.lst = NULL,
  route = c("bolus", "oral", "infusion"),
  dose_type = NULL,
  pooled_ctrl = pooled_control(),
  ssctrl = ss_control()
)

Arguments

Details

Estimates individual apparent volumes of distribution from observed peak concentrations. Individual estimates are then summarized to obtain a population-level value.

For single-dose data, Vd is calculated according to the route of administration:

• Bolus: $V_d = \mathrm{Dose} / C_{\mathrm{max}}$

• Infusion: $V_d = (\mathrm{Rate} \times t_{\mathrm{inf}}) / C_{\mathrm{max}}$

• Oral: $V_d = (\mathrm{Dose} \times F) / C_{\mathrm{max}}$, where $F = 1 - e^{-k_a t}$

For multiple-dose data, observed Cmax values are adjusted to single-dose equivalents using the accumulation ratio:

$R_{\mathrm{ac}} = \frac{1}{1 - e^{-k_e \tau}}, \quad k_e = \ln(2)/t_{1/2}$

Adjusted values are used to estimate Vd using the same route-specific equations.

Value

A list containing individual and population Vd estimates and related dose-level data.

Author(s)

Zhonghui Huang

See Also

run_single_point_base, trimmed_geom_mean, pooled_control, ss_control

Examples

# Process dataset
out <- processData(Bolus_1CPT)
# Get half-life and dose route
hf <- get_hf(dat = out$dat)$half_life_median
rt <- out$Datainfo$Value[out$Datainfo$Infometrics == "Dose Route"]
# Estimate Vd
approx.vc(dat = out$dat, half_life = hf, route = rt)$approx.vc.value

Description

Bins data by time using either equal-frequency (quantile) binning or algorithmic binning methods.

Usage

bin.time(
  dat,
  nbins = "auto",
  bin.method = c("quantile", "jenks", "kmeans", "pretty", "sd", "equal", "density")
)

Arguments

Details

Supports quantile-based binning and other data-driven methods (jenks, kmeans, pretty, sd, equal, density), with optional automatic bin count selection.

Value

A list containing summary results of the time-concentration binning process.

Author(s)

Zhonghui Huang

See Also

vpc::auto_bin

Examples

dat <- Bolus_1CPT
dat <- nmpkconvert(dat)
dat <- calculate_tad(dat)
dat$DVstd <- dat$DV / dat$dose
bin.time(dat)

Description

Calculates clearance using an adaptive single-point pharmacokinetic method

Usage

calculate_cl(
  dat,
  half_life = NULL,
  dose_type = NULL,
  pooled_ctrl = pooled_control(),
  ssctrl = ss_control()
)

Arguments

Details

Estimates individual and population clearance from steady-state pharmacokinetic data. If half-life is not provided, it is estimated from pooled data using get_hf() and pooling rules defined in pooled_control().

The procedure:

• Identifies steady-state observations using is_ss() and ss_control() criteria.

• Selects peak and trough concentrations within each dose interval to represent steady-state behavior.

• Classifies concentration points as Cssmax, Cssmin, or Cssavg based on timing within the interval and decay pattern.

• Computes individual clearance as Dose / (Cssavg × tau).

• Aggregates individual clearance values using a trimmed geometric mean to obtain a population estimate.

Supports bolus, infusion, and oral administration routes.

Value

A list containing:

• dat: the processed dataset with steady-state identification

• cl_df: individual clearance estimates

• trimmed_mean_cl: the population clearance calculated as a trimmed geometric mean with a 5 percent trimming level to reduce the impact of outliers

Author(s)

Zhonghui Huang

See Also

get_hf, get_pooled_data, pooled_control, is_ss, ss_control, trimmed_geom_mean

Examples

dat <- processData(Bolus_1CPT)$dat
calculate_cl(dat, get_hf(dat)$half_life_median)$trimmed_mean_cl

Description

Calculate time after dose (TAD) for pharmacokinetic observations.

Usage

calculate_tad(dat, verbose = FALSE)

Arguments

Details

The procedure identifies dosing events based on the event identifier (EVID) and assigns each observation the attributes of the most recent prior dose. The time after dose is then calculated for observation rows. If dose_number column is not present in the input, it is automatically created for each subject.

Value

A modified data frame with added columns:

• tad: time after dose, calculated as the observation time minus the time of the most recent prior dose; set to NA for dosing records

• iiobs: interdose interval inherited from the most recent dosing record

• rateobs: infusion rate inherited from the most recent dosing record

• routeobs (optional): route of administration inherited from the most recent dosing record, included only if route information is present

• dose_number: sequential dose number, generated if not already present

Author(s)

Zhonghui Huang

Examples

calculate_tad(Bolus_1CPT)
calculate_tad(Infusion_1CPT)
calculate_tad(Oral_1CPT)

Description

Calculates the volume of distribution (Vd) using an adaptive single-point approach

Usage

calculate_vd(
  dat,
  half_life = NULL,
  dose_type = NULL,
  pooled_ctrl = pooled_control(),
  route = c("bolus", "oral", "infusion")
)

Arguments

Details

The function uses a concentration observed within the first 20% of the elimination half-life after dosing as the early point for estimating the volume of distribution.

$Vd = \frac{\text{Dose}}{C_0}$

For infusion:

$Vd = \frac{\text{Rate} \times \min(\text{TIME}, \text{durationobs})}{C_0}$

Here, $C_0$ represents the early concentration observed within the first 20% of the elimination half-life after dosing, which is used as an approximation of the initial concentration for estimating volume of distribution (Vd). TIME refers to time after dose; durationobs is the actual infusion duration.

When half_life is not provided, it is estimated from pooled data using the functions get_pooled_data() and get_hf().

Value

A list with two elements:

• vd_df: individual volume of distribution estimates

• trimmed_mean_vd: population volume of distribution estimated as a trimmed geometric mean using a 5 percent trimming level

Author(s)

Zhonghui Huang

See Also

get_pooled_data, get_hf, trimmed_geom_mean

Examples

dat <- Bolus_1CPT
out <- processData(dat)
fdat<- out$dat
froute <-out$Datainfo$Value[out$Datainfo$Infometrics == "Dose Route"]
half_life <- get_hf(dat = fdat)$half_life_median
calculate_vd(dat = fdat, half_life = half_life,route=froute)$trimmed_mean_vd

Description

Computes predictive error metrics by comparing simulated and observed concentration–time data using specified pharmacokinetic parameters and dosing route.

Usage

eval_perf_1cmpt(
  dat,
  est.method = "rxSolve",
  ka = NULL,
  cl = NULL,
  vd = NULL,
  route = c("bolus", "infusion", "oral"),
  ncores = 2
)

Arguments

Details

Internally selects the appropriate one-compartment model fitting function, using Fit_1cmpt_oral() for oral administration and Fit_1cmpt_iv() for intravenous administration. Predictive performance is quantified using the metrics.() function.

Value

A numeric vector containing absolute prediction error, mean absolute error, mean absolute percentage error, root mean square error, and relative root mean square error.

See Also

Fit_1cmpt_oral, Fit_1cmpt_iv, metrics.

Examples

eval_perf_1cmpt(
  dat = pheno_sd,
  est.method = "rxSolve",
  cl = 0.006,
  vd = 1,
  route = "bolus"
)

Description

Control settings for fallback rules in parameter estimation

Usage

fallback_control(
  enable_ka_fallback = TRUE,
  sigma_method_additive = "model",
  sigma_method_proportional = "model",
  sigma_fallback_fraction = 0.2
)

Arguments

Value

A list of fallback control parameters.

Examples

fallback_control()

Description

Identifies the optimal terminal phase for lambdaz estimation using a systematic log-linear regression approach with adjusted R-squared optimization criteria.

Usage

find_best_lambdaz(
  time,
  conc,
  route = "bolus",
  duration = NULL,
  adj_r_squared_threshold = 0.7,
  nlastpoints = 3,
  tolerance = 1e-04
)

Arguments

Details

The algorithm implements the following decision logic:

1. Identifies the time of maximum observed concentration (Tmax)

2. Defines candidate terminal phases starting from the last 3 measurable concentrations

3. Iteratively evaluates longer time spans by including preceding data points

4. For each candidate phase:

   • Performs log-concentration vs. time linear regression

   • Requires negative regression slope (positive $\lambda_z$)

   • Calculates adjusted R-squared metric

5. Selects the optimal phase based on:

   • Highest adjusted R-squared value

   • When R-squared differences are < tolerance, selects the fit with more points

6. Validates final selection against R-squared threshold

Value

A list containing:

• lambdaz: Estimated terminal elimination rate constant ($\lambda_z$), or NA if no valid fit

• UsedPoints: Number of data points used in the optimal fit

• adj.r.squared: Adjusted R-squared value ($R^2$) of the optimal regression

• message: Character vector containing diagnostic messages or warnings

Author(s)

Zhonghui Huang

Examples

# Basic usage
time <- c(0.5, 1, 2, 4, 6, 8, 10)
conc <- c(12, 8, 5, 3, 2, 1.5, 1)
find_best_lambdaz(time, conc)

# With infusion route specification
find_best_lambdaz(time, conc, route = "bolus",duration=1)

# Custom threshold settings
find_best_lambdaz(time, conc, adj_r_squared_threshold = 0.8, tolerance = 0.001)

Description

Fits intravenous (IV) pharmacokinetic data to a one-compartment model with first-order elimination using the naive pooled data approach. Supports multiple estimation methods provided by nlmixr2 and can optionally return only predicted concentrations to support efficient simulation workflows.

Usage

Fit_1cmpt_iv(
  data,
  est.method,
  input.cl,
  input.vd,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with a single column cp (predicted concentrations). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Bolus_1CPT
# Run simulation
Fit_1cmpt_iv(
  data = dat,
  est.method = "rxSolve",
  input.cl = 4,
  input.vd = 70,
  input.add = 1
)
# Return only predicted concentrations
Fit_1cmpt_iv(
 data = dat,
 est.method = "rxSolve",
 input.cl = 4,
 input.vd = 70,
 input.add = 0,
 return.pred.only = TRUE
)

Description

Fits intravenous (IV) pharmacokinetic data to a one-compartment model with Michaelis-Menten (nonlinear) elimination using the naive pooled data approach. Supports multiple estimation methods available in nlmixr2, and optionally returns only predicted concentrations to reduce memory use in simulation workflows.

Usage

Fit_1cmpt_mm_iv(
  data,
  est.method,
  input.vmax,
  input.km,
  input.vd,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with a single column cp (predicted concentrations). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Bolus_1CPTMM
# Run simulation
Fit_1cmpt_mm_iv(
  data = dat,
  est.method = "rxSolve",
  input.vmax = 1000,
  input.km = 250,
  input.vd = 70,
  input.add = 10)

# Return only predicted concentrations
Fit_1cmpt_mm_iv(
  data = dat,
  est.method = "rxSolve",
  input.vmax = 1000,
  input.km = 250,
  input.vd = 70,
  input.add = 0,
  return.pred.only = TRUE
  )

Description

Fits oral pharmacokinetic data to a one-compartment model with first-order absorption and Michaelis-Menten (nonlinear) elimination using the naive pooled data approach. Supports multiple estimation methods available in nlmixr2, and optionally returns only predicted concentrations to reduce memory use in simulation workflows.

Usage

Fit_1cmpt_mm_oral(
  data,
  est.method,
  input.ka,
  input.vmax,
  input.km,
  input.vd,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with columns cp (predicted concentration) and DV (observed data). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Oral_1CPTMM
# Run simulation
Fit_1cmpt_mm_oral(
  data = dat,
  est.method = "rxSolve",
  input.ka = 1,
  input.vmax = 1000,
  input.km = 250,
  input.vd = 70,
  input.add = 10
)
# Return only predicted concentrations
Fit_1cmpt_mm_oral(
  data = dat,
  est.method = "rxSolve",
  input.ka = 1,
  input.vmax = 1000,
  input.km = 250,
  input.vd = 70,
  input.add = 10
)

Description

Fits oral pharmacokinetic data to a one-compartment model with first-order absorption and first-order elimination using the naive pooled data approach. Supports multiple estimation methods provided by nlmixr2 and can optionally return only predicted concentrations to support efficient simulation workflows.

Usage

Fit_1cmpt_oral(
  data,
  est.method,
  input.ka,
  input.cl,
  input.vd,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with a single column cp (predicted concentrations). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Oral_1CPT
# Run simulation
Fit_1cmpt_oral(
  data = dat,
  est.method = "rxSolve",
  input.ka = 1,
  input.cl = 4,
  input.vd = 70,
  input.add = 10
)
# Return only predicted concentrations
Fit_1cmpt_oral(
  data = dat,
  est.method = "rxSolve",
  input.ka = 1,
  input.cl = 4,
  input.vd = 70,
  input.add = 0,
  return.pred.only = TRUE
)

Description

Fits intravenous (IV) pharmacokinetic data to a two-compartment model with first-order elimination using the naive pooled data approach. Supports multiple estimation methods provided by nlmixr2 and can optionally return only predicted concentrations to support efficient simulation workflows.

Usage

Fit_2cmpt_iv(
  data,
  est.method,
  input.cl,
  input.vc2cmpt,
  input.vp2cmpt,
  input.q2cmpt,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with a single column cp (predicted concentrations). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Bolus_2CPT
# Run simulation
Fit_2cmpt_iv(
  data = dat,
  est.method = "rxSolve",
  input.cl = 4,
  input.vc2cmpt = 70,
  input.vp2cmpt = 40,
  input.q2cmpt = 4,
  input.add = 10
)
# Return only predicted concentrations
Fit_2cmpt_iv(
  data = dat,
  est.method = "rxSolve",
  input.cl = 4,
  input.vc2cmpt = 70,
  input.vp2cmpt = 40,
  input.q2cmpt = 4,
  input.add = 0,
  return.pred.only = TRUE
)

Description

Fits oral pharmacokinetic data to a two-compartment model with first-order absorption and first-order elimination using the naive pooled data approach. Supports multiple estimation methods available in nlmixr2, and optionally returns only predicted concentrations to support simulation workflows.

Usage

Fit_2cmpt_oral(
  data,
  est.method,
  input.ka,
  input.cl,
  input.vc2cmpt,
  input.vp2cmpt,
  input.q2cmpt,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with a single column cp (predicted concentrations). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Oral_2CPT[Oral_2CPT$ID<11,]
# Run simulation
Fit_2cmpt_oral(
  data = dat,
  est.method = "rxSolve",
  input.ka = 1,
  input.cl = 4,
  input.vc2cmpt = 70,
  input.vp2cmpt = 40,
  input.q2cmpt = 10,
  input.add = 10
)

Description

Fits intravenous (IV) pharmacokinetic data to a three-compartment model with linear (first-order) elimination using the naive pooled data approach. Supports multiple estimation methods provided by nlmixr2 and can optionally return only predicted concentrations to support efficient simulation workflows.

Usage

Fit_3cmpt_iv(
  data,
  est.method,
  input.cl,
  input.vc3cmpt,
  input.vp3cmpt,
  input.vp23cmpt,
  input.q3cmpt,
  input.q23cmpt,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with a single column cp (predicted concentrations). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Bolus_2CPT
# Run simulation
Fit_3cmpt_iv(
  data = dat,
  est.method = "rxSolve",
  input.cl = 4,
  input.vc3cmpt = 70,
  input.vp3cmpt = 35,
  input.vp23cmpt = 5,
  input.q3cmpt = 4,
  input.q23cmpt = 4,
  input.add = 10
)
# Return only predicted concentrations
Fit_3cmpt_iv(
  data = dat,
  est.method = "rxSolve",
  input.cl = 4,
  input.vc3cmpt = 70,
  input.vp3cmpt = 35,
  input.vp23cmpt = 35,
  input.q3cmpt = 4,
  input.q23cmpt = 4,
  input.add = 10,
  return.pred.only = TRUE
)

Description

Fits oral pharmacokinetic data to a three-compartment model with first-order absorption and first-order elimination using the naive pooled data approach. Supports multiple estimation methods provided by nlmixr2 and can optionally return only predicted concentrations to support efficient simulation workflows.

Usage

Fit_3cmpt_oral(
  data,
  est.method,
  input.ka,
  input.cl,
  input.vc3cmpt,
  input.vp3cmpt,
  input.vp23cmpt,
  input.q3cmpt,
  input.q23cmpt,
  input.add,
  ncores = 2,
  return.pred.only = FALSE,
  ...
)

Arguments

Value

If return.pred.only = TRUE, returns a data.frame with a single column cp (predicted concentrations). Otherwise, returns a fitted model object produced by nlmixr2.

Author(s)

Zhonghui Huang

Examples

dat <- Oral_2CPT[Oral_2CPT$ID<11,]
Fit_3cmpt_oral(
  data = dat,
  est.method = "rxSolve",
  input.ka = 1,
  input.cl = 4,
  input.vc3cmpt = 70,
  input.vp3cmpt = 35,
  input.vp23cmpt = 35,
  input.q3cmpt = 4,
  input.q23cmpt = 4,
  input.add = 10
)

Description

Estimates the terminal elimination rate constant (lambda_z) of a pharmacokinetic profile. The function first attempts to use the find_best_lambdaz method. If no valid estimate is obtained, it falls back to a simplified log-linear regression using progressively fewer data points to enforce a negative slope.

Usage

force_find_lambdaz(time, conc, ...)

Arguments

Details

This function implements a two-step strategy to ensure estimation of the terminal elimination slope:

• First, it applies find_best_lambdaz to automatically select the best fitting terminal phase segment based on adjusted R-squared optimization.

• If find_best_lambdaz fails (e.g., limited data), the function forcibly fits simplified linear models using progressively fewer points (starting from n-1 down to 2) until a negative slope is identified. In fallback mode, adjusted R-squared is not considered.

Value

A list containing:

• lambdaz: Estimated terminal elimination rate constant (1/time)

• intercept: Intercept of the log-linear regression, used to extrapolate concentration at time zero

• method: Method used (find_best_lambdaz or fallback regression)

• UsedPoints: Number of time-concentration points used for estimation

• adj.r.squared: Adjusted R-squared (available only when using find_best_lambdaz)

• message: Diagnostic message summarizing the outcome

• slopefit: Fitted linear model object

Author(s)

Zhonghui Huang

See Also

find_best_lambdaz

Examples

time <- c(0.5, 1, 2, 4, 6, 8, 10)
conc <- c(12, 8, 5, 3, 2, 1.5, 1)
force_find_lambdaz(time, conc)

Description

Estimates the terminal half-life of a drug using pooled pharmacokinetic data. The method supports analysis based on first-dose, repeated-dose, or combined dosing profiles.

Usage

get_hf(dat, dose_type = "first_dose", pooled = NULL, verbose = TRUE, ...)

Arguments

Details

The function estimates terminal half-life using the following procedure:

• Generate or use existing pooled pharmacokinetic data

• Identify the terminal phase using elimination slope estimation

• Calculate the terminal elimination rate constant (lambda_z)

• Derive half-life using:

$t_{1/2} = \frac{\log(2)}{\lambda_z}$

Value

A list containing individual and median half-life estimates for first-dose, repeated-dose, and combined dosing profiles.

Author(s)

Zhonghui Huang

See Also

get_pooled_data, bin.time, find_best_lambdaz

Examples

dat <- Bolus_1CPT
dat <- processData(dat)$dat
get_hf(dat, dose_type = "combined_doses")

Description

Processes pharmacokinetic data and produces pooled datasets according to the dosing context. Data can be grouped based on first dose, repeated dosing, or a combination of both, with control over binning and time alignment.

Usage

get_pooled_data(
  dat,
  dose_type = c("first_dose", "repeated_doses", "combined_doses"),
  pooled_ctrl = pooled_control()
)

Arguments

Details

For repeated-doses and combined-doses classifications, the most common interdose interval is identified from dosing records and used to determine whether observations fall within the relevant interval. If tad_rounding is TRUE, both time after dose and dosing interval are rounded before comparison.

Value

A list containing pooled pharmacokinetic datasets depending on the specified dose type:

• datpooled_fd: pooled data for first-dose observations

• datpooled_efd: pooled data for repeated dosing

• datpooled_all: pooled data combining first-dose and repeated-dose observations

Author(s)

Zhonghui Huang

See Also

pooled_control, trimmed_geom_mean

Examples

dat <- processData(Bolus_1CPT)$dat
get_pooled_data(dat, dose_type = "combined_doses")

Description

Calculates key pharmacokinetic parameters using non-compartmental methods for both intravenous and oral administration data.

Usage

getnca(
  x,
  y,
  dose = 1,
  trapezoidal.rule = c("linear_up_log_down", "linear"),
  ss = 0,
  duration = NULL,
  nlastpoints = 3,
  slope.method = c("bestfitforce", "bestfit"),
  route = c("bolus", "oral", "infusion")
)

Arguments

Value

A list containing:

• cl - Clearance (CL), calculated as Dose/AUC

• vz - volume of distribution (Vz), calculated as CL / lambdaz

• half_life - Terminal elimination half-life, computed as ln(2) / lambdaz

• auct - Area under the concentration–time curve from time 0 to last measurable concentration

• auc0_inf - AUC extrapolated to infinity

• C_last - Last non-zero measurable concentration

• lambdaz - Terminal elimination rate constant

• aumc_0_t - Area under the first moment curve from time 0 to last measurable concentration

• aumc_0_inf - AUMC extrapolated to infinity

• used_points - Number of time–concentration points used to estimate lambdaz

• adj.r.squared - Adjusted R-squared of the terminal phase regression

• messages - Warning or diagnostic messages returned during the calculation

Examples

# IV bolus example
dat <- data.frame(TIME = c(0.5, 1, 2, 4, 6, 8),
                  DV = c(12, 8, 5, 3, 2, 1))
getnca(x = dat$TIME, y = dat$DV, dose = 1)

# IV infusion example
dat <- data.frame(TIME = c(0.5, 1, 2, 4, 6, 8),
                  DV = c(2, 8, 5, 3, 2, 1))
getnca(x = dat$TIME, y = dat$DV, dose = 1, route = "infusion", duration = 1)

# Oral administration example
dat <- data.frame(TIME = c(0, 1, 2, 4, 6, 8),
                  DV = c(0, 9, 12, 8, 6, 2))
getnca(x = dat$TIME, y = dat$DV, route = "oral")

Description

This function constructs a combined table containing:

• ETA variances (e.g., eta.cl, eta.vc), which represent inter-individual variability (IIV) in pharmacokinetic parameters;

• Derived covariances (e.g., cov.eta_cl_vc) computed from ETA variances and assumed pairwise correlations.

Usage

getOmegas()

Details

ETA variances are initialized to 0.1 by default. Correlations within defined omega blocks (block 1: eta.vmax, eta.km; block 2: eta.cl, eta.vc, eta.vp, eta.vp2, eta.q, eta.q2) are assumed to be 0.1 and used to compute covariances as:

$Cov(i, j) = sqrt(Var_i) * sqrt(Var_j) * Corr(i, j)$

The resulting output format aligns with Recommended_initial_estimates.

Value

A data.frame with columns: Parameters, Methods, and Values.

Examples

getOmegas()

Description

Provides a unified and fully automated workflow to generate initial pharmacokinetic and residual variability parameters for population PK models using concentration–time data from bolus, infusion, or oral administration.

Usage

getPPKinits(dat, control = initsControl(), ncores = 2, verbose = TRUE)

Arguments

Details

The pipeline integrates four model-informed analytical components applied to raw or pooled concentration–time profiles:

1. Adaptive single-point methods

2. Naive pooled graphic methods

3. Naive pooled non-compartmental analysis (NCA) with optional Wagner–Nelson Ka calculation for oral dosing

4. Parameter sweeping across one-, two-, three-compartment and Michaelis–Menten models

In addition to structural PK parameters, the framework also initializes statistical model components:

• Inter-individual variability (IIV): pragmatic fixed $\omega^2$ values are assigned to random effects.

• Residual unexplained variability (RUV): estimated either using a data-driven method based on trimmed residual summaries or a fixed-fraction approach consistent with NONMEM User Guide recommendations.

• Model applicability: the automated and model-informed strategy generates robust initial values suitable for both linear and nonlinear mixed-effects pharmacokinetic models.

Value

An object of class getPPKinits containing recommended initial parameter estimates, intermediate results, and computation diagnostics.

Author(s)

Zhonghui Huang

See Also

initsControl, run_single_point, run_graphcal, run_pooled_nca, sim_sens_1cmpt_mm, sim_sens_2cmpt, sim_sens_3cmpt, metrics.

Examples

getPPKinits(pheno_sd[pheno_sd$ID<11,])

Description

Applies getsigmas to each individual and dose group after filtering observation records (EVID == 0), and calculates trimmed mean estimates of additive and proportional residual variability.

Usage

getsigma(df, nlastpoints = 3, sigma_trim = 0.05)

Arguments

Details

The function groups the dataset by subject and dose occasion, applies elimination-phase residual analysis using getsigmas, and summarizes the individual residual standard deviations by their trimmed means. This provides population-level estimates of additive and proportional residual unexplained variability (RUV).

Value

A list containing:

• summary: Named list with trimmed mean values of additive and proportional residual variability

• full: Data frame with residual estimates for each individual-dose group

Author(s)

Zhonghui Huang

See Also

getsigmas

Examples

dat <- Bolus_1CPT
dat <- processData(dat)$dat
getsigma(dat)

Description

Performs log-linear regression on the elimination phase of a single individual's or one group's pharmacokinetic concentration–time data to estimate additive and proportional residual standard deviations.

Usage

getsigmas(group_df, nlastpoints = 3)

Arguments

Details

Residuals are computed from individual-predicted concentrations (IPRED) and observed concentrations (DV) using the following definitions:

$\sigma_{add} = \sqrt{Var(C_{obs} - C_{pred})}$

$\sigma_{prop} = \sqrt{Var\left(\frac{C_{obs}}{C_{pred}} - 1\right)}$

where $C_{obs}$ is the observed concentration and $C_{pred}$ is the model-predicted concentration obtained by back-transformation of the log-linear regression. The additive residual standard deviation ($\sigma_{add}$) and proportional residual standard deviation ($\sigma_{prop}$) are calculated per individual.

Value

A tibble with the following columns:

• intercept: Intercept of the log-linear regression line

• slope: Estimate of the terminal elimination rate constant

• residual_sd_additive: Standard deviation of additive residuals

• residual_sd_proportional: Standard deviation of proportional residuals

Author(s)

Zhonghui Huang

Examples

dat <- Bolus_1CPT
dat <- processData(dat)$dat
getsigmas(dat[dat$ID == 1 & dat$dose_number == 1 & dat$resetflag == 1 &
              dat$EVID == 0, ])

Description

Estimates clearance (CL), volume of distribution (Vd), terminal slope (lambdaz), and extrapolated concentration at time zero (C0exp) from intravenous pharmacokinetic data using graphical methods.

Usage

graphcal_iv(dat, dose = 1, ...)

Arguments

Details

Terminal slope (lambdaz) is estimated using force_find_lambdaz(), which applies an automated phase selection strategy with fallback regression when required.

Value

A list containing graphical estimates of CL, Vd, lambda_z, and C0exp.

Author(s)

Zhonghui Huang

See Also

force_find_lambdaz

Examples

dat <- data.frame(TIME = c(0.5, 1, 2, 4, 6, 8, 10),
                  DV = c(12, 8, 5, 3, 2, 1.5, 1))
graphcal_iv(dat, dose = 100)

Description

Estimates key pharmacokinetic parameters from oral concentration–time data using graphical methods, including absorption rate constant (ka), elimination rate constant (kel), terminal slope, extrapolated concentration (C0exp), apparent volume of distribution (Vd/F), and clearance (Cl/F).

Usage

graphcal_oral(dat, dose = 1, ...)

Arguments

Details

The terminal slope (lambdaz) is estimated using force_find_lambdaz(). The apparent volume of distribution and clearance are computed using the following relationships:

$Vd/F = \frac{Dose \times ka}{C_0 \times (ka - kel)}$

$Cl/F = kel \times Vd/F$

where ka is estimated from the absorption phase.

Value

A list containing graphical estimates of ka, kel, lambda_z, C0exp, Vd/F, and Cl/F.

Author(s)

Zhonghui Huang

See Also

find_best_lambdaz

Examples

dat <- data.frame(TIME = c(0.5, 1, 2, 4, 6, 8, 10),
                  DV = c(1, 2, 5, 3, 2, 1.5, 1))
graphcal_oral(dat, dose = 100, route = "oral")

Description

Constructs a grid of all combinations of ka, cl, and vd parameters from different sources (e.g., simpcal, graph, NCA methods), and removes combinations that are redundant based on relative tolerance. Only oral routes consider ka value for deduplication. Any parameter value set that includes NA is removed up front.

Usage

hybrid_eval_perf_1cmpt(
  route = "bolus",
  dat,
  sp_out_ka,
  sp_out_cl,
  sp_out_vd,
  graph_out_ka,
  graph_out_cl,
  graph_out_vd,
  nca_fd_ka,
  nca_fd_cl,
  nca_fd_vd,
  nca_efd_ka,
  nca_efd_cl,
  nca_efd_vd,
  nca_all_ka,
  nca_all_cl,
  nca_all_vd,
  ncores = 2,
  verbose = TRUE
)

Arguments

Value

A data.frame of unique parameter combinations with source labels and values.

Examples

dat <- Oral_1CPT[Oral_1CPT$ID<11,]
# Example parameter estimates from different methods
sp_out_ka <- 1.2; sp_out_cl <- 3.5; sp_out_vd <- 50
graph_out_ka <- 1.1; graph_out_cl <- 3.6; graph_out_vd <- 52
nca_fd_ka <- 1.3; nca_fd_cl <- 3.4; nca_fd_vd <- 49
nca_efd_ka <- NA;  nca_efd_cl <- NA;  nca_efd_vd <- NA
nca_all_ka <- 1.25; nca_all_cl <- 3.55; nca_all_vd <- 51
# Run hybrid evaluation
 hybrid_eval_perf_1cmpt(
  route = "oral",
  dat = dat,
  sp_out_ka = sp_out_ka, sp_out_cl = sp_out_cl, sp_out_vd = sp_out_vd,
  graph_out_ka = graph_out_ka, graph_out_cl = graph_out_cl, graph_out_vd = graph_out_vd,
  nca_fd_ka = nca_fd_ka, nca_fd_cl = nca_fd_cl, nca_fd_vd = nca_fd_vd,
  nca_efd_ka = nca_efd_ka, nca_efd_cl = nca_efd_cl, nca_efd_vd = nca_efd_vd,
  nca_all_ka = nca_all_ka, nca_all_cl = nca_all_cl, nca_all_vd = nca_all_vd,
  verbose = FALSE
)

Description

Aggregates modular control functions into a structured list for use in population pharmacokinetic parameter initialization.

Usage

initsControl(
  ss.control = ss_control(),
  pooled.control = pooled_control(),
  nca.control = nca_control(),
  fallback.control = fallback_control(),
  selmetrics = "rRMSE2",
  hybrid.base = TRUE,
  preferNCA = TRUE
)

Arguments

Value

A named list combining all control modules for parameter estimation.

See Also

ss_control, pooled_control, nca_control, fallback_control

Examples

initsControl(
  pooled.control = pooled_control(nbins = 8),
  fallback.control = fallback_control(
    sigma_method_additive = "fixed_fraction"
  )
)

Description

Evaluates whether pharmacokinetic observations have reached steady state based on user-defined control settings. The classification can be based on a fixed number of doses, the number of half-lives relative to the dosing interval, or a combination of both criteria.

Usage

is_ss(df, ssctrl = ss_control(), half_life = NA)

Arguments

Details

The function determines steady state by examining each observation in relation to prior dosing history. The required number of doses is calculated based on the specified method in ss_control(). Observation times are evaluated to confirm that dose interval and dose amount variability fall within acceptable limits and that the time after dose is within the most recent dosing interval. Observations manually marked as steady state using SSflag are also recognized as steady state.

Value

A data frame with added columns indicating steady-state status, the dosing interval for steady-state observations, and the method used to classify steady state.

See Also

ss_control()

Examples

dat <- pheno_sd
dat <- processData(dat)$dat
out <- is_ss(df = dat)
out[out$SteadyState == TRUE & !is.na(out$SteadyState),
    c("ID", "TIME", "DV", "EVID", "SteadyState")]

Description

This estimates the absorption rate constant in a multiple-dose oral model using first-order pharmacokinetics.

Usage

ka_calculation_md(cl, ke, t, Ct, Fbio = 1, Dose, tau)

Arguments

Details

The value of ka is obtained numerically using the uniroot unction by solving the following equation:

$Ct = \frac{Fbio \cdot Dose \cdot ka}{Vd \cdot (ka - ke)} \left( \frac{e^{-ke \cdot t}}{1 - e^{-ke \cdot \tau}} - \frac{e^{-ka \cdot t}}{1 - e^{-ka \cdot \tau}} \right)$

ka is estimated using uniroot(), which solves for the root of the residual function (predicted Ct - observed Ct) within a bounded interval (ka > ke and ka <= 1000)

Value

A list containing the following components:

Author(s)

Zhonghui Huang

Examples

# Example from Oral_1CPT dataset (ID = 1, 5th dose, t = 2 h)
ka_calculation_md(cl = 4, ke = 0.057, t = 2, Ct = 852, Dose = 60000, tau = 24)

Description

This estimates the absorption rate constant in a single-dose oral model using first-order pharmacokinetics.

Usage

ka_calculation_sd(cl, ke, t, Ct, Fbio = 1, Dose)

Arguments

Details

The model assumes a one-compartment structure with first-order absorption and first-order elimination.

The concentration-time relationship is:

$Ct = \frac{Fbio \cdot Dose \cdot ka}{Vd \cdot (ka - ke)} \left( e^{-ke \cdot t} - e^{-ka \cdot t} \right)$

where the volume of distribution is defined as:

$Vd = \frac{cl}{ke}$

ka is estimated using uniroot(), which solves for the root of the residual function (predicted Ct - observed Ct) within a bounded interval (ka > ke and ka <= 1000)

Value

A list containing:

Author(s)

Zhonghui Huang

Examples

# Example from Oral_1CPT dataset (ID = 1, 1st dose, t = 0.5 h)
ka_calculation_sd(cl = 3.62, ke = 0.0556, t = 0.5, Ct = 310.6, Dose = 60000)

Description

Calculates absorption rate constant using the Wagner–Nelson method for single-dose extravascular pharmacokinetics.

Usage

ka_wanger_nelson(dat, nca.out = NULL)

Arguments

Details

The Wagner-Nelson method estimates the fraction of drug absorbed over time based on the principle of mass balance, where the unabsorbed fraction is quantified as the proportion of the administered dose that has not yet entered systemic circulation. A linear regression is applied to the natural logarithm of the unabsorbed fraction versus time, and the negative slope of this regression corresponds to the first-order absorption rate constant 'ka'.

Key assumptions:

• Single-dose oral or extravascular administration

• First-order absorption and first-order elimination

• Linear pharmacokinetics with 'ka' greater than 'ke'

Computational steps:

• AUC is calculated using trapezoidal integration.

• The fraction absorbed is calculated from AUC and the terminal elimination rate constant.

• The remaining fraction is transformed using the natural logarithm.

• Linear regression of log(remaining fraction) against time yields 'ka'.

Value

A list containing:

• ka: Estimated absorption rate constant

• dat_out_wanger_nelson: Input data frame augmented with calculated pharmacokinetic variables including cumulative AUC, fraction absorbed, and fraction remaining

Author(s)

Zhonghui Huang

References

Wagner JG and Nelson E (1963). Percent absorbed time plots derived from blood level and/or urinary excretion data. Journal of Pharmaceutical Sciences, 52(6), 610-611.

Examples

# Simulated one-compartment oral absorption data
Dose <- 100
Fbio <- 1
Vd   <- 70
CL   <- 4
ka   <- 1.2
ke   <- CL / Vd
t  <- seq(0.5, 8, by = 0.5)
Ct <- (Fbio * Dose * ka) / (Vd * (ka - ke)) * (exp(-ke * t) - exp(-ka * t))

dat <- data.frame(TIME = t, DV = Ct)

ka_wanger_nelson(dat)

Description

Assigns sequential dose numbers based on dosing events (EVID) within each subject.

Usage

mark_dose_number(dat)

Arguments

Value

A modified data frame with an added column named dose_number, indicating the sequential dose count within each subject and reset group.

Author(s)

Zhonghui Huang

Examples

mark_dose_number(Bolus_1CPT)
mark_dose_number(Infusion_1CPT)
mark_dose_number(Oral_1CPT)

Description

Computes common error metrics that quantify the predictive performance of pharmacometric models by comparing predicted (pred.x) and observed (obs.y) concentration values.

Usage

metrics.(pred.x, obs.y)

Arguments

Details

The function stops with an error if pred.x and obs.y have unequal lengths. The following metrics are calculated:

$APE = \sum |pred.x - obs.y|$

Absolute prediction error (APE) is the sum of absolute differences.

$MAE = \frac{1}{n} \sum |pred.x - obs.y|$

Mean absolute error (MAE) expresses the average absolute deviation.

$MAPE = \frac{100}{n} \sum \left| \frac{pred.x - obs.y}{obs.y} \right|$

Mean absolute percentage error (MAPE) normalizes the error by observed values.

$RMSE = \sqrt{\frac{1}{n} \sum (pred.x - obs.y)^2}$

Root mean squared error (RMSE) penalizes larger deviations.

$rRMSE1 = \frac{RMSE}{\bar{obs.y}} \times 100$

Relative RMSE type 1 is the RMSE normalized by the mean observed value.

$rRMSE2 = 100 \times \sqrt{\frac{1}{n} \sum \left( \frac{pred.x - obs.y}{(pred.x + obs.y)/2} \right)^2}$

Relative RMSE type 2 is symmetric and normalizes by the mean of each predicted–observed pair.

Value

A numeric vector with named elements:

• APE: absolute prediction error

• MAE: mean absolute error

• MAPE: mean absolute percentage error

• RMSE: root mean squared error

• rRMSE1: relative RMSE (type 1)

• rRMSE2: relative RMSE (type 2)

Examples

obs.y  <- rnorm(100, mean = 100, sd = 10)
pred.x <- obs.y + rnorm(100, mean = 0, sd = 5)
metrics.(pred.x = pred.x, obs.y = obs.y)

Description

Control options for non-compartmental analysis (NCA)

Usage

nca_control(
  trapezoidal.rule = c("linear_up_log_down", "linear"),
  duration = NULL,
  nlastpoints = 3,
  slope.method = "bestfitforce"
)

Arguments

Value

A list with NCA control parameters.

Author(s)

Zhonghui Huang

Examples

nca_control()

Description

Expands dosing records that contain additional doses (ADDL) using the specified interdose interval (II). Each additional dose is converted into an explicit record to provide a complete dosing history suitable for population pharmacokinetic modeling.

Usage

nmpkconvert(dat)

Arguments

Details

Dosing records with ADDL greater than zero are expanded using the formula: TIME_new = TIME + n × II, where n ranges from 1 up to ADDL. Observation records (EVID = 0) are not modified.

Value

A data frame with expanded dosing records. The columns ADDL and II are reset to zero after expansion.

Examples

# Dataset with a single subject and additional dosing
dat <- data.frame(
  ID   = rep(1, 6),
  EVID = c(1, 0, 0, 1, 0, 0),
  ADDL = c(2, 0, 0, 0, 0, 0),
  TIME = c(0, 1, 2, 3, 4, 5),
  II   = c(24, 0, 0, 0, 0, 0),
  AMT  = c(100, 0, 0, 0, 0, 0)
)
nmpkconvert(dat)

Description

Defines control parameters for time binning and preprocessing in pooled data analysis. These parameters are typically passed to 'get_pooled_data'.

Usage

pooled_control(
  nbins = 10,
  bin_method = c("quantile", "jenks", "kmeans", "pretty", "sd", "equal", "density"),
  tad_rounding = TRUE
)

Arguments

Value

A named list containing control parameters for pooled pharmacokinetic analysis.

See Also

get_pooled_data

Examples

pooled_control()

Description

Prints a summary of the results from the initial parameter estimation pipeline, including recommended initial estimates, ETA variance estimates, and parameter descriptions. It is the default S3 print method for objects of class getPPKinits.

Usage

## S3 method for class 'getPPKinits'
print(x, ...)

Arguments

Value

Prints a formatted summary to the console.

Examples

## Oral example
inits.out <- getPPKinits(Bolus_1CPT)
print(inits.out)

Description

Processes a time–concentration dataset to derive analysis-ready variables and structured output for pharmacokinetic evaluation.

Usage

processData(dat, verbose = TRUE)

Arguments

Details

This function standardizes and preprocesses time–concentration data to ensure compatibility with pharmacokinetic modeling workflows in nlmixr2. The operations follow these steps:

1. Standardize data

   • convert column names to uppercase

   • coerce key columns (TIME, DV, EVID, AMT, RATE, etc.) to numeric

2. Process events and observations

   • impute EVID from MDV if missing

   • handle censored data (CENS) by converting them to excluded records

   • remove or recode invalid EVID values (e.g., DV = 0 observations)

3. Expand dose events

   • expand dosing records using nmpkconvert() when ADDL and II are present

   • assign dose occasions using mark_dose_number()

4. Determine administration route and infusion logic

   • derive RATE and DUR when needed

   • identify route (bolus, infusion, oral) based on compartment and rate

5. Generate derived variables

   • calculate time after dose using calculate_tad()

   • compute dose-normalized concentration (DVstd)

   • flag eligible records for terminal elimination phase

6. Summarize dataset

   • classify dataset as first-dose, repeated-dose, or mixed

   • generate summary metrics for nlmixr2 analysis

   Classification of dosing context is based on pharmacokinetic observation records (EVID equal to 0), determining whether observed concentrations occur after the first dose, during repeated dosing, or across both contexts. The categories are:

   • first_dose: observations occur only after the initial administration, without repeated-dose or steady-state intervals.

   • repeated_doses: observations occur only after multiple administrations or under steady-state conditions.

   • combined_doses: observations include both first-dose and repeated-dose intervals and are analyzed together.

Value

A list with two elements:

• dat: A data frame containing the processed time–concentration dataset with standardized and derived pharmacokinetic variables, including resetflag, SSflag, route, dose_number, DVstd, indiv_lambda_z_eligible, and others.

• Datainfo: A data frame summarizing the dataset structure, including subject counts and observation counts for first-dose and multiple-dose conditions, with contextual notes.

Author(s)

Zhonghui Huang

See Also

nmpkconvert, mark_dose_number, calculate_tad

Examples

dat <- Bolus_1CPT
processData(dat)

Description

Performs graphical estimation of pharmacokinetic parameters based on pooled concentration–time data and the specified route of administration.

Usage

run_graphcal(
  dat,
  route,
  dose_type = c("first_dose", "repeated_doses", "combined_doses"),
  pooled = NULL,
  pooled_ctrl = pooled_control(),
  ...
)

Arguments

Details

The function pools individual profiles using get_pooled_data() when needed, and then applies route-specific graphical methods (graphcal_iv or graphcal_oral) to estimate parameters such as clearance, volume of distribution, terminal slope, and absorption rate constant (for oral data).

Value

A list containing graphical estimates of key pharmacokinetic parameters.

Author(s)

Zhonghui Huang

See Also

graphcal_iv, graphcal_oral, get_pooled_data

Examples

# Example 1 (iv case)
dat <- Bolus_1CPT
dat <- processData(dat)$dat
run_graphcal(dat, route="bolus")

# Example 2 (oral case)
dat <- Oral_1CPT
dat <- processData(dat)$dat
run_graphcal(dat, route="oral")

# Example 3 (infusion case).
# Approximate calculation. only use when the infusion duration is very short

dat <- Infusion_1CPT
dat <- processData(dat)$dat
run_graphcal(dat, route="infusion")

Description

It implements pointwise estimation of absorption rate constants for single-dose and multiple-dose pharmacokinetic models.

Usage

run_ka_solution(df, cl, ke, Fbio = 1)

Arguments

Details

For each subject, the time of maximum observed concentration (Tmax) is identified as the time corresponding to the highest DV. Only records with TIME less than or equal to Tmax are retained, representing the absorption phase.

Two scenario-specific calculations are implemented: single-dose and multiple-dose at steady state.

• For single-dose data (dose_number == 1 and SteadyState == FALSE), the function uses ka_calculation_sd(), which applies a one-compartment oral absorption model under first-order absorption and elimination.

• For steady-state multiple-dose data (dose_number > 1 and SteadyState == TRUE), the function uses ka_calculation_md(), which accounts for accumulation using the dosing interval (dose_interval).

This function does not perform model fitting. The median is recommended for use in pharmacokinetic modeling.

Value

A list with the following elements:

ka_calc_median

Median ka value across all valid observations.

ka_calc_dat_sd

Data frame containing absorption-phase single-dose data, with estimated ka and diagnostic messages.

ka_calc_dat_md

Data frame containing absorption-phase steady-state multiple-dose data, with ka estimates.

ka_calc_dat

Combined data frame (single-dose and multiple-dose) containing all ka estimates.

Author(s)

Zhonghui Huang

Examples

# Single-dose
df <- Oral_1CPT[Oral_1CPT$SD == 1, ]
df <- processData(df)$dat
df <- is_ss(df)
run_ka_solution(df = df, cl = 4, ke = 4/70, Fbio = 1)$ka_calc_median

# Mixed doses
dat <- Oral_1CPT
df_ss <- processData(dat)$dat
df_ss <- is_ss(df_ss)
run_ka_solution(df = df_ss, cl = 4, ke = 4/70, Fbio = 1)$ka_calc_median

Description

Implements pooled concentration–time profiling followed by non-compartmental analysis (NCA) to derive pharmacokinetic parameters across single-dose, multiple-dose, or combined dosing scenarios under bolus, oral, or infusion routes.

Usage

run_pooled_nca(
  dat,
  route = c("bolus", "oral", "infusion"),
  dose_type = c("first_dose", "repeated_doses", "combined_doses"),
  pooled = NULL,
  pooled_ctrl = pooled_control(),
  nca_ctrl = nca_control()
)

Arguments

Details

The function first pools individual subject data into representative concentration–time profiles using get_pooled_data based on the settings in pooled_ctrl. The pooled profiles are then passed to getnca, which computes non-compartmental parameters using rules specified in nca_ctrl.

Value

A list containing NCA results according to the selected dose_type.

Author(s)

Zhonghui Huang

See Also

get_pooled_data, bin.time, getnca

Examples

out   <- processData(Bolus_1CPT)
dat   <- out$dat
route <- out$Datainfo$Value[out$Datainfo$Infometrics == "Dose Route"]

run_pooled_nca(
  dat       = dat,
  dose_type = "first_dose",
  route     = route
)$nca.fd.results

Description

Runs full adaptive single-point pharmacokinetic analysis to estimate CL, Vd, and ka across bolus, oral, and infusion dosing scenarios.

Usage

run_single_point(
  dat,
  route = c("bolus", "oral", "infusion"),
  half_life = NULL,
  dose_type = NULL,
  pooled_ctrl = pooled_control(),
  ssctrl = ss_control()
)

Arguments

Value

An object of class "single.point.lst" with results from the base and extended steps.

Author(s)

Zhonghui Huang

See Also

run_single_point_base, run_single_point_extra

Examples

# Example: Adaptive single-point PK analysis for bolus data
# Step 1: Preprocess the data
dat <- Oral_1CPT
out <- processData(dat)
# Step 2: Extract route and dose type info
froute <- out$Datainfo$Value[out$Datainfo$Infometrics == "Dose Route"]
fdose_type <- out$Datainfo$Value[out$Datainfo$Infometrics == "Dose Type"]
# Step 3: Estimate half life
half_life <- get_hf(dat = out$dat)$half_life_median
# Step 4: Run single-point analysis (CL, Vd, Ka if oral)
result <- run_single_point(
  dat = out$dat,
  route = froute,
  dose_type = fdose_type,
  half_life = half_life
)
# Step 5: View results
print(result$singlepoint.results)

Description

Implements adaptive single-point pharmacokinetic analysis to calculate clearance and volume of distribution.

Usage

run_single_point_base(
  dat,
  route = c("bolus", "oral", "infusion"),
  half_life = NULL,
  dose_type = NULL,
  pooled_ctrl = pooled_control(),
  ssctrl = ss_control()
)

Arguments

Details

This function integrates clearance and volume estimation into a unified adaptive workflow, using steady-state pharmacokinetic observations and trimmed mean statistics to reduce the influence of outliers.

Value

A list containing:

• summary: a data frame with trimmed mean clearance and volume of distribution, and run time information

• dat: the processed dataset used for analysis

• cl_df: individual clearance estimates

• vd_df: individual volume of distribution estimates

See Also

calculate_cl, calculate_vd, pooled_control, ss_control

Examples

dat <- Bolus_1CPT
out <- processData(dat)
fdat <- out$dat
route <- out$Datainfo$Value[out$Datainfo$Infometrics == "Dose Route"]
half_life <- get_hf(dat = fdat)$half_life_median
run_single_point_base(dat = fdat, half_life = half_life, route = route)$summary

Description

Extended single-point pharmacokinetic analysis for deriving CL, Vd, and ka

Usage

run_single_point_extra(
  dat = NULL,
  half_life = NULL,
  single_point_base.lst = NULL,
  route = c("bolus", "oral", "infusion"),
  dose_type = NULL,
  pooled_ctrl = pooled_control(),
  ssctrl = ss_control()
)

Arguments

Details

The function derives pharmacokinetic parameters using the following logic:

• When both clearance (CL) and volume of distribution (Vd) are available from the base calculation, these values are directly used without modification.

• If Vd is missing but CL and elimination half-life are provided, Vd is calculated using:

  $V_d = \frac{CL \cdot t_{1/2}}{\ln(2)}$

• If CL is missing but Vd and half-life are available, CL is calculated using:

  $CL = \frac{V_d \cdot \ln(2)}{t_{1/2}}$

• If both CL and Vd are unavailable but half-life is provided, Vd is estimated using dose and Cmax:

  $V_d = \frac{\mathrm{Dose}}{C_{\mathrm{max}}}$

  and CL is subsequently derived:

  $CL = \frac{V_d \cdot \ln(2)}{t_{1/2}}$

• For oral administration, the absorption rate constant (ka) is estimated using a solution-based approach implemented in run_ka_solution(). Only concentration–time data from the absorption phase are used, defined as time after dose (tad) less than 20% of the terminal half-life and occurring prior to Tmax, where absorption is the dominant process.

The function supports bolus, oral, and infusion administration routes. For oral dosing, only data within the absorption phase are used to estimate the absorption rate constant (ka), specifically using concentration-time observations prior to the maximum concentration (Tmax).

Value

A list containing:

• singlepoint.results: A data frame with estimated ka, CL, Vd, computation start time, processing time, and a descriptive message of the applied logic.

• dat: The dataset used for processing.

• single_point.ka.out: Output used for estimating the absorption rate constant (for oral administration), if applicable.

• single_point_cl_df: Data used for clearance estimation.

• single_point_vd_df: Data used for volume of distribution estimation.

• approx.vc.out: Data used for estimating the volume of distribution from maximum concentration (Cmax) and dose when needed.

Author(s)

Zhonghui Huang

See Also

run_single_point_base, run_single_point, run_ka_solution

Examples

dat <- Bolus_1CPT
out <- processData(dat)
fdat <- out$dat
froute <- out$Datainfo$Value[out$Datainfo$Infometrics == "Dose Route"]
half_life <- get_hf(dat = fdat)$half_life_median
run_single_point_extra(
  dat = fdat,
  half_life = half_life,
  single_point_base.lst = run_single_point_base(
    dat = fdat,
    half_life = half_life,
    route = froute
  ),
  route = froute
)

Description

Performs parameter sweeping by varying pharmacokinetic parameters in a one-compartment model with Michaelis-Menten elimination.

Usage

sim_sens_1cmpt_mm(
  dat,
  sim_vmax = list(mode = "auto", values = NULL, est.cl = NULL),
  sim_km = list(mode = "auto", values = NULL),
  sim_vd = list(mode = "manual", values = NULL),
  sim_ka = list(mode = "manual", values = NULL),
  route = c("iv", "oral"),
  ncores = 2,
  verbose = TRUE
)

Arguments

Details

The function generates a parameter grid and performs model fitting for each combination using Fit_1cmpt_mm_iv. Parameters can be specified manually or automatically derived. Model predictions and fit metrics are computed for each simulation to assess parameter sensitivity.

Value

A data frame containing parameter combinations and model fit metrics.

Author(s)

Zhonghui Huang

See Also

Fit_1cmpt_mm_iv, Fit_1cmpt_mm_oral

Examples

# Example: IV dosing scenario with automatic Vmax and Km
out <- sim_sens_1cmpt_mm(
  dat = Bolus_1CPTMM[Bolus_1CPTMM$ID<50,],
  sim_vmax = list(mode = "auto", est.cl = 4),
  sim_km   = list(mode = "auto"),
  sim_vd   = list(mode = "manual", values = 70),
  sim_ka   = list(mode = "manual", values = NA),
  route = "iv"
)
head(out[out$rRMSE2==min(out$rRMSE2),])

Description

Performs parameter sweeping by varying pharmacokinetic parameters in a two-compartment model under IV or oral dosing. Model fit is evaluated across combinations of CL, Vc, Vp, Q, and Ka (oral only).

Usage

sim_sens_2cmpt(
  dat,
  sim_ka = list(mode = "manual", values = NULL),
  sim_cl = list(mode = "manual", values = NULL),
  sim_vc = list(mode = "manual", values = NULL),
  sim_vp = list(mode = c("auto", "manual"), values = NULL),
  sim_q = list(mode = c("auto", "manual"), values = NULL, auto.strategy = c("scaled",
    "fixed")),
  route = c("iv", "oral"),
  ncores = 2,
  verbose = TRUE
)

Arguments

Details

The function generates a parameter grid and performs model fitting for each combination using Fit_2cmpt_iv or Fit_2cmpt_oral. Parameters can be specified manually or automatically derived. Model predictions and fit metrics are computed for each simulation to assess parameter sensitivity.

Value

A data frame containing parameter combinations with model fit metrics.

Author(s)

Zhonghui Huang

See Also

Fit_2cmpt_iv, Fit_2cmpt_oral

Examples

out <- sim_sens_2cmpt(
  dat = Bolus_2CPT[Bolus_2CPT$ID<6,],
  sim_cl = list(mode = "manual", values = 4),
  sim_vc = list(mode = "manual", values = 50),
  sim_vp = list(mode = "auto"),
  sim_q  = list(mode = "auto"),
  sim_ka = list(mode = "manual", values = NA),
  route = "iv",verbose=FALSE
)
head(out[out$rRMSE2==min(out$rRMSE2),])

Description

Performs parameter sweeping by varying pharmacokinetic parameters in a three-compartment model under IV or oral dosing. Parameter combinations include Vc, Vp1, Vp2, Q1, Q2, CL, and Ka (oral only).

Usage

sim_sens_3cmpt(
  dat,
  sim_vc = list(mode = "manual", values = NULL),
  sim_vp = list(mode = c("auto", "manual"), values = NULL),
  sim_vp2 = list(mode = c("auto", "manual"), values = NULL),
  sim_q = list(mode = c("auto", "manual"), values = NULL, auto.strategy = c("scaled",
    "fixed")),
  sim_q2 = list(mode = c("auto", "manual"), values = NULL, auto.strategy = c("scaled",
    "fixed")),
  sim_cl = list(mode = "manual", values = NULL),
  sim_ka = list(mode = "manual", values = NULL),
  route = c("iv", "oral"),
  ncores = 2,
  verbose = TRUE
)

Arguments

Details

The function generates a parameter grid and evaluates each combination using Fit_3cmpt_iv or Fit_3cmpt_oral. Model predictions and fit metrics are calculated for each simulation to assess parameter influence and identify optimal regions of the parameter space. Parameters can be provided manually or derived automatically.

Value

A data frame containing parameter combinations with model fit metrics.

Author(s)

Zhonghui Huang

See Also

Fit_3cmpt_iv, Fit_3cmpt_oral

Examples

out <- sim_sens_3cmpt(
  dat = Bolus_2CPT[Bolus_2CPT$ID<6,],
  sim_cl = list(mode = "manual", values = 4),
  sim_vc = list(mode = "manual", values = 50),
  sim_vp = list(mode = "auto"),
  sim_vp2 = list(mode = "auto"),
  sim_q  = list(mode = "auto", auto.strategy = "scaled"),
  sim_q2 = list(mode = "auto", auto.strategy = "scaled"),
  route = "iv",verbose=FALSE
)
head(out[out$rRMSE2==min(out$rRMSE2),])

Description

Constructs a list of control parameters used by is_ss() to determine pharmacokinetic steady state.

Usage

ss_control(
  ss_method = c("combined", "fixed_doses", "half_life_based"),
  no.doses = 5,
  no.half_lives = 5,
  allowed_interval_variation = 0.25,
  allowed_dose_variation = 0.2,
  min_doses_required = 3,
  tad_rounding = TRUE
)

Arguments

Value

A named list containing the steady-state control parameters, typically passed as the ssctrl argument to is_ss().

See Also

is_ss

Examples

ss_control()
ss_control(ss_method = "fixed_doses", no.doses = 4)

Description

Computes the area under the curve (AUC) or the area under the moment curve (AUMC) using the linear trapezoidal rule. If moment = TRUE, the function estimates AUMC by integrating time * concentration.

Usage

trapezoidal_linear(x, y, moment = FALSE)

Arguments

Value

A numeric value representing the estimated AUC or AUMC using the linear trapezoidal rule.

Examples

x <- c(0.5, 1, 2, 4, 6, 8)
y <- c(12, 8, 5, 3, 2, 1)
trapezoidal_linear(x, y)                # AUC
trapezoidal_linear(x, y, moment = TRUE) # AUMC

Description

Computes the area under the curve (AUC) or the area under the moment curve (AUMC) using a hybrid trapezoidal rule. The method uses linear interpolation for increasing or constant concentration segments, and logarithmic interpolation for decreasing segments.

Usage

trapezoidal_linear_up_log_down(x, y, moment = FALSE)

Arguments

Details

If moment = TRUE, the function calculates the area under the moment curve (AUMC), i.e., it integrates t * C(t) over time instead of just C(t).

Value

A numeric value representing the estimated AUC or AUMC using the linear-up/log-down trapezoidal method.

Examples

x <- c(0, 0.5, 1, 2, 4, 6, 8)
y <- c(0, 2, 8, 5, 3, 2, 1)
trapezoidal_linear_up_log_down(x, y)                # AUC
trapezoidal_linear_up_log_down(x, y, moment = TRUE) # AUMC

Description

Computes the trimmed geometric mean of a numeric vector

Usage

trimmed_geom_mean(x, trim = 0, na.rm = TRUE)

Arguments

Value

A numeric value representing the trimmed geometric mean. Returns NA if no values remain after trimming.

Examples

x <- c(1, 2, 3, 4, 5, 100)
trimmed_geom_mean(x, trim = 0.05)