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Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1–15), followed by RIF40 (days 16–30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%–115%); tolbutamide, 80% (74%–86%); omeprazole, 55% (47%–65%); dextromethorphan, 77% (68%–86%); midazolam, 62% (49%–78%), and 117% (105%–130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

The pharmacokinetics (PK) of ethanol are important in pharmacology and therapeutics because of potential drug-alcohol interactions as well as in forensic science when alcohol-related crimes are investigated. The PK of ethanol have been extensively studied since the 1930s, although some issues remain unresolved, such as the significance of first-pass metabolism, whether zero-order kinetics apply, and the effects of food on bioavailability. We took advantage of nonlinear mixed-effects modeling to describe blood-alcohol concentration (BAC) profiles derived from 3 published clinical studies involving oral, intraduodenal, and intravenous administration of ethanol with and without food. The overall data set included 1510 BACs derived from 72 healthy subjects (60 men, 12 women) aged between 20 and 60 years. Two-compartment models with first-order absorption and Michaelis-Menten elimination kinetics adequately described the BAC profiles. Food intake had 2 separate effects: It reduced the absorption rate constant and accelerated the maximum elimination rate. Estimates of the maximum elimination rate (fasted) and the food effect (as a factor) were 6.31 g/h (95%CI, 6.04-6.59 g/h) and 1.39-fold (95%CI, 1.33-1.46-fold), respectively. Simulations showed that the area under the BAC-time curve (AUC) was smaller with lower input rate of ethanol, irrespective of any first-pass metabolism. The AUC from time 0 to 10 hours for a 75-kg subject was 2.34 g center dot h/L (fed) and 3.83 g center dot h/L (fasted) after an oral dose of 45 g ethanol. This difference was mainly attributable to the food effect on ethanol elimination and depended less on the absorption rate. Our new approach to explain the complex human PK of ethanol may help when BAC predictions are made in clinical pharmacology and forensic medicine.

Purpose Although temozolomide is widely used in the treatment of childhood central nervous system (CNS) tumors, information on its pharmacokinetic profile in the brain or cerebrospinal fluid (CSF) is sparse. This study aimed at investigating whether measurable and clinically relevant concentrations of temozolomide are reached and maintained in CSF for continuous oral administration in pediatric patients. A population pharmacokinetic model was developed to quantify CSF penetration of temozolomide. Methods Eleven pediatric CNS tumor patients (aged 4-14 years) treated with oral temozolomide using a metronomic schedule (24-77 mg/m(2)/day) were included. Temozolomide concentrations in 28 plasma samples and 64 CSF samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modeling and simulations were performed using non-linear mixed effects modeling (NONMEM 7.4.2). Results Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24-5.99) mu g/ml and 0.37 (0.06-1.76) mu g/ml, respectively. A two-compartment model (central/plasma [1], CSF [2]) with first-order absorption, first-order elimination, and a transit compartment between CSF and plasma adequately described the data. Population mean estimates for clearance (CL) and the volume of distribution in the central compartment (V-c) were 3.29 L/h (95% confidence interval (CI) 2.58-3.95) and 10.5 L (8.17-14.32), respectively. Based on simulations, we found a median area under the concentration vs. time curve ratio (AUC(CSF) / AUC(plasma) ratio) of 37%. Conclusion Metronomic oral temozolomide penetrates into the CSF in pediatric patients, with even higher concentration levels compared to adults.

This study provides a whole-body physiologically-based pharmacokinetic (PBPK) model of dextromethorphan and its metabolites dextrorphan and dextrorphan O-glucuronide for predicting the effects of cytochrome P450 2D6 (CYP2D6) drug-gene interactions (DGIs) on dextromethorphan pharmacokinetics (PK). Moreover, the effect of interindividual variability (IIV) within CYP2D6 activity score groups on the PK of dextromethorphan and its metabolites was investigated. A parent-metabolite-metabolite PBPK model of dextromethorphan, dextrorphan, and dextrorphan O-glucuronide was developed in PK-Sim and MoBi. Drug-dependent parameters were obtained from the literature or optimized. Plasma concentration-time profiles of all three analytes were gathered from published studies and used for model development and model evaluation. The model was evaluated comparing simulated plasma concentration-time profiles, area under the concentration-time curve from the time of the first measurement to the time of the last measurement (AUC(last)) and maximum concentration (C-max) values to observed study data. The final PBPK model accurately describes 28 population plasma concentration-time profiles and plasma concentration-time profiles of 72 individuals from four cocktail studies. Moreover, the model predicts CYP2D6 DGI scenarios with six of seven DGI AUC(last) and seven of seven DGI C-max ratios within the acceptance criteria. The high IIV in plasma concentrations was analyzed by characterizing the distribution of individually optimized CYP2D6 k(cat) values stratified by activity score group. Population simulations with sampling from the resulting distributions with calculated log-normal dispersion and mean parameters could explain a large extent of the observed IIV. The model is publicly available alongside comprehensive documentation of model building and model evaluation.