Kok-Yong Seng

Population pharmacokinetics of caffeine in healthy male adults using mixed‐effects models

Objective:  Caffeine has been shown to maintain or improve the performance of individuals, but its pharmacokinetic profile for Asians has not been well characterized. In this study, a population pharmacokinetic model for describing the pharmacokinetics of caffeine in Singapore males was developed. The data were also analysed using non‐compartmental models.

CYP3A5*3 and bilirubin predict midazolam population pharmacokinetics in Asian cancer patients.

We aim to evaluate the influence of covariates, including cytochrome P450 3A (CYP3A) genetic polymorphisms, on the pharmacokinetics of midazolam (MDZ) in Asian cancer patients, using a population pharmacokinetic approach. Pharmacokinetic data were obtained from 24 adult cancer patients who received an intravenous bolus dose of 1 mg MDZ as a CYP3A phenotyping probe, 1‐day before starting FOLFIRI chemotherapy. Concentrations of MDZ and its major metabolites, 1′‐hydroxymidazolam (1OHM) and 1′‐hydroxymidazolam glucuronide (HMG) were measured using liquid chromatography/mass spectrometry. The population pharmacokinetic study was conducted using NONMEM. Demographics, clinical characteristics, and genetic polymorphisms were screened as covariates. A two‐compartment model for MDZ and two sequential compartments representing 1OHM and HMG best described the data. The CYP3A5*3 and total bilirubin level significantly influenced MDZ clearance. The population typical MDZ clearance for CYP3A5*3 expressers was 22% lower than non‐expressers. Baseline bodyweight was a statistically significant covariate for clearance and distribution volume of 1OHM. Creatinine clearance was positively correlated with HMG clearance. Our data indicate that CYP3A5*3, total bilirubin, bodyweight, and creatinine clearance are important predictors of MDZ and metabolite pharmacokinetics. Further studies in more patients are needed to explore the links between the identified covariates and the disposition of MDZ and its metabolites.

Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults

OBJECTIVES Rifampicin is a first-line anti-TB drug. The objectives of this analysis were to evaluate the population pharmacokinetics of rifampicin and its partly active metabolite, 25-deacetyl-rifampicin, with and without isoniazid, and to identify covariates that may explain variability in their disposition under steady-state conditions. METHODS Thirty-four healthy Asian subjects were randomized to receive rifampicin (600 mg) or rifampicin (600 mg)/isoniazid (300 mg) daily for 14 days. After a 14 day washout, subjects were switched over to rifampicin (600 mg)/isoniazid (300 mg) or rifampicin (600 mg) daily. Plasma concentration-time data were analysed using NONMEM to estimate population pharmacokinetic parameters and evaluate relationships between parameters and demographic factors, and metabolic enzyme, transporter and transcriptional regulator genotypes. Allometric scaling of clearance and volume of distribution terms based on body weight was applied. RESULTS A one-compartment model in which absorption was described by a transit absorption model best described the rifampicin data. 25-Deacetyl-rifampicin pharmacokinetic data were best described by a two-compartment model linked to the rifampicin model. None of the investigated covariates significantly influenced the disposition of rifampicin and 25-deacetyl-rifampicin. The apparent clearance of rifampicin and 25-deacetyl-rifampicin was estimated at 10.3 [relative standard error (RSE) 5.6%] and 95.8 (RSE 10%) L/h, respectively, for 70 kg adults. CONCLUSIONS The pharmacokinetics of rifampicin and its main metabolite were characterized. Prospective studies with a larger number of participants, including patients, are needed to validate the results of this study.

Population pharmacokinetics and pharmacogenetics of alcohol in Chinese and Indians in Singapore

What is known and Objective: Interindividual variability in alcohol pharmacokinetics is influenced by a number of factors, including polymorphisms in genes mediating alcohol pharmacology, ethnicity, sex and body size. Several studies have evaluated the population pharmacokinetics of alcohol from breath alcohol measures. None of these studies, however, have evaluated ethnicity and alcohol‐metabolizing enzyme genotypes as covariates in their population pharmacokinetic modelling. We aimed to develop a population pharmacokinetic model using clinical and genetic factors and to identify covariates that influenced interindividual variability in alcohol clearance and volume of distribution.

Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophosphate-induced toxicity in mice and rats

A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was recently developed to study the effect of diisopropylfluorophosphate (DFP) on acetylcholinesterase (AChE) activity in mouse and rat. That model takes into account relatively complex interactions involving many parameters, some of which may be uncertain and/or highly variable, especially those characterizing AChE activity after DFP intoxication. The primary objective of this study was to identify parameters that contribute most to the variability of AChE dynamics for model optimization against data. For this purpose, the influence of the variability of the rate constants for synthesis (Ksyn) and degradation (Kdeg) of AChE, and regeneration (Kreg) and aging (Kage) of inhibited AChE on the variability of AChE activity in mice and rat venous blood and brain was first calculated by a global sensitivity analysis. Next, the mouse PBPK/PD model was calibrated by optimizing the values of Ksyn, Kdeg, Kreg and Kage. Thereafter, scale-up of the DFP-induced AChE activity was performed from mouse to rat. Validation of the rat model was performed by comparing the time course of venous blood and brain AChE activities from a Monte Carlo analysis to those obtained in vivo. Sensitivity analysis on the verified models showed that Kreg and Ksyn were the most influential factors of AChE activity at shorter and longer durations, respectively, after DFP challenge. Scale-up of the AChE dynamics from mouse to rat was also successful, as evidenced by significant overlapping between the predicted 95th percentile confidence intervals and the experimental data.

Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

ABSTRACT In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤ Cmax ≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

Calibration and validation of a physiologically based model for soman intoxication in the rat, marmoset, guinea pig and pig

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model has been developed for low, medium and high levels of soman intoxication in the rat, marmoset, guinea pig and pig. The primary objective of this model was to describe the pharmacokinetics of soman after intravenous, intramuscular and subcutaneous administration in the rat, marmoset, guinea pig, and pig as well as its subsequent pharmacodynamic effects on blood acetylcholinesterase (AChE) levels, relating dosimetry to physiological response. The reactions modelled in each physiologically realistic compartment are: (1) partitioning of C(±)P(±) soman from the blood into the tissue; (2) inhibition of AChE and carboxylesterase (CaE) by soman; (3) elimination of soman by enzymatic hydrolysis; (4) de novo synthesis and degradation of AChE and CaE; and (5) aging of AChE–soman and CaE–soman complexes. The model was first calibrated for the rat, then extrapolated for validation in the marmoset, guinea pig and pig. Adequate fits to experimental data on the time course of soman pharmacokinetics and AChE inhibition were achieved in the mammalian models. In conclusion, the present model adequately predicts the dose–response relationship resulting from soman intoxication and can potentially be applied to predict soman pharmacokinetics and pharmacodynamics in other species, including human. Copyright

Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males

Objectives We have characterised the population pharmacokinetics‐pharmacodynamics of pyridostigmine given as pyridostigmine bromide.

Tracking body core temperature in military thermal environments: An extended Kalman filter approach

Military personnel operating in hot and humid environments are susceptible to heat-related illnesses. As heat-related illnesses are associated with a rise in body core temperature (Tc), a reliable system for real-time assessment of Tc is useful to minimize heat casualties. However, invasive measurement of Tc (such as rectal, intestinal and esophageal temperature) is impractical in the field settings. This paper describes the model construction and qualification results of tracking Tc using an extended Kalman filter (EKF) based on physiological data recorded from wearable sensors. Tc, surface skin temperature (Tsk) and heart rate (HR) data were collected from three studies with different experimental protocols, climatic conditions and soldier volunteers. The predictive performance of the model was evaluated by cross-validation and external validation. The final EKF model was implemented using a nonlinear (cubic) state-space model (Tsk versus Tc) with a stage-wise, autoregressive exogenous model (incorporating HR) as the time update model. Overall, when tested against an independent dataset, the model showed a prediction bias of 0.11°C, a root mean square deviation of 0.29°C, and 87% of all Tc predictions fell within ±0.3°C of the measured Tc values. The results from our study indicate that the derived EKF model is accurate enough to calculate subject-specific Tc for the minimization of heat injuries.

Nonlinear mixed effects modelling for the analysis of longitudinal body core temperature data in healthy volunteers.

Many longitudinal studies have collected serial body core temperature (T c) data to understand thermal work strain of workers under various environmental and operational heat stress environments. This provides the opportunity for the development of mathematical models to analyse and forecast temporal T c changes across populations of subjects. Such models can reduce the need for invasive methods that continuously measure T c. This current work sought to develop a nonlinear mixed effects modelling framework to delineate the dynamic changes of T c and its association with a set of covariates of interest (e.g. heart rate, chest skin temperature), and the structure of the variability of T c in various longitudinal studies. Data to train and evaluate the model were derived from two laboratory investigations involving male soldiers who participated in either a 12 (N  =  18) or 15 km (N  =  16) foot march with varied clothing, load and heat acclimatisation status. Model qualification was conducted using nonparametric bootstrap and cross validation procedures. For cross validation, the trajectory of a new subjects T c was simulated via Bayesian maximum a posteriori estimation when using only the baseline T c or using the baseline T c as well as measured T c at the end of every work (march) phase. The final model described T c versus time profiles using a parametric function with its main parameters modelled as a sigmoid hyperbolic function of the load and/or chest skin temperature. Overall, T c predictions corresponded well with the measured data (root mean square deviation: 0.16 °C), and compared favourably with those provided by two recently published Kalman filter models.