Assessment of body mass-related covariates for rifampicin pharmacokinetics in healthy Caucasian volunteers.

PURPOSE: Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). METHODS: Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600 mg of rifampicin separated by a wash-out period of at least 9 days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. RESULTS: A one-compartment model with nonlinear (Michaelis-Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. CONCLUSION: Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin.

A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.

INTRODUCTION: Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. OBJECTIVE: This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. METHODS: Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. RESULTS: Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). CONCLUSION: The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.

Absorption, pharmacokinetics, and safety of triclosan after dermal administration.

We evaluated the pharmacokinetics and safety of the antimicrobial agent triclosan after dermal application of a 2% triclosan-containing cream to six volunteers. Percutaneous absorption calculated from urinary excretion was 5.9% +/- 2.1% of the dose (mean +/- standard deviation). The amount absorbed suggests that daily application of a standard adult dose would result in a systemic exposure 890 times lower than the relevant no-observed-adverse-effect level. Triclosan can be considered safe for use in hydrophobic creams.

Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler.

Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and interoccasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown.

A novel toxicokinetic modeling of cypermethrin and permethrin and their metabolites in humans for dose reconstruction from biomarker data.

To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA) in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor) along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data.

Pharmacokinetics, pharmacodynamics, and comparative bioavailability of single, oral 2-mg doses of dexamethasone liquid and tablet formulations: a randomized, controlled, crossover study in healthy adult volunteers.

BACKGROUND: Dexamethasone is a glucocorticoid used widely worldwide for immunosuppressive treatment, allergies, bronchiolitis, and croup, among others. For children, liquid formulations are especially suitable because, compared with other dosage forms, both exact dosing and proper intake are facilitated. OBJECTIVE: The objective was to evaluate the pharmacokinetics, pharmacodynamics, and comparative bioavailability of a commercial liquid oral dexamethasone formulation intended for pediatric use relative to those of a tablet. METHODS: In a randomized, controlled, crossover study in 24 healthy adult volunteers, we administered single doses of the liquid and tablet formulation, containing 2 mg of dexamethasone each. Blood samples were taken up to 24 hours postdose. Quantification was carried out using a validated specific and sensitive high-pressure liquid chromatography with UV detector method. Noncompartmental pharmacokinetic parameters were compared between treatments according to European Medicines Agency (EMA) bioequivalence guidelines. For AUC(0-t) and C(max), the 90% CI for the ratio of the test and reference products should be contained within the predetermined acceptance interval of 80% to 125%. As a pharmacodynamic variable, we measured suppression of endogenous cortisol (predose and postdose). RESULTS: Both preparations showed similar pharmacokinetic and pharmacodynamic profiles but high between-subject variability of pharmacokinetic key parameters and endogenous cortisol concentrations (>30%). Mean AUC(0-t), AUC(0-∞), and C(max) were 37.8 ng/mL/h, 46.0 ng/mL/h, and 9.35 ng/mL, respectively, for the liquid and 41.3 ng/mL/h, 48.1 ng/mL/h, and 9.17 ng/mL, respectively, for the tablet formulation. T(max) was 0.89 hour (liquid) and 0.97 hour (tablet). The point estimates and 90% CIs for AUC(0-t), AUC(0-∞), and C(max) ratios (liquid vs tablet) were 91.42% (82.05%-101.86%), 95.72% (84.46%-108.5%), and 102.04% (86.94%-119.76%), respectively. Thus, point estimates and 90% CIs were within the bioequivalence range of 80% to 125% for all relevant parameters, including the pharmacodynamic parameter AUEC (area under the effect curve). CONCLUSIONS: This single-dose study suggests that the test and reference products met the EMA regulatory criteria to assume bioequivalence in these fasting healthy male and female volunteers. German Register of Clinical Trials registration number: DRKS00000785.

Inhibition of CYP 17, a new strategy for the treatment of prostate cancer.

Androgens are growth factors for approximately 80 percent of all prostate cancers. Suppressing androgen biosynthesis is therefore an important therapeutic strategy in order to inhibit tumor growth. Unfortunately, the drugs currently applied to lower androgen levels only affect testicular androgen production. Since androgens are also synthesized in the adrenal glands, tumor stimulation cannot be blocked completely. A new therapeutic target, CYP 17 (P450 17, 17alpha-hydroxylase-C17, C20 lyase), is likely to improve this situation. CYP 17 is a P450 enzyme and catalyzes the last step of androgen biosynthesis in both testes and adrenals. Inhibition of this enzyme will therefore result in a complete block of androgen production. This paper gives an overview of the current situation in this novel field of drug research and focuses on the development of steroidal and non-steroidal inhibitors of CYP 17.