- Related lesson: 3.4 Placenta and breast milk
Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Maternal Plasma and Breast Milk & Infant Cord Blood and Plasma: A Model-Based Analysis of Mother-Infant Pairs for Tuberculosis Prevention
In the IMPAACT 2001 study, the ratio of breast milk to maternal plasma concentration was 0.0236 for rifapentine and 0.0411 for its metabolite desacetyl rifapentine, and the estimated maximum relative infant dose was below 1%. Rifapentine crossed the placenta, but the authors judge the infant plasma concentrations unlikely to be clinically significant.
- Related lesson: 4.2 CYP enzymes
Unbound Intrinsic Formation Clearance of 6β-Hydroxycortisol Is a Useful Biomarker of CYP3A4 Activity during Pregnancy
In 47 women, the unbound intrinsic formation clearance of 6β-hydroxycortisol increased 1.8-fold in late pregnancy, which corresponds to a 2.1-fold increase in hepatic CYP3A activity. The authors propose this endogenous biomarker for future studies of CYP3A activity across pregnancy and postpartum.
- Related lesson: 4.2 CYP enzymes
Dose-dependent Effects of Cenobamate on Brivaracetam Pharmacokinetics: A Retrospective Cohort Study
In 891 samples from 213 patients, low cenobamate doses (12.5 to 50 mg/day) increased serum brivaracetam concentrations by 32%, and high doses (250 to 450 mg/day) decreased them by 21%. Cenobamate inhibits CYP2C19, an enzyme of brivaracetam metabolism, and the authors ask for prospective studies of the clinical relevance.
- Related lesson: 4.2 CYP enzymes
Change in clobazam pharmacokinetics after introduction of cenobamate
In 10 patients with drug-resistant focal epilepsy, the clobazam dose was reduced by a mean of 74% during cenobamate titration, and the combined level of clobazam and its active metabolite N-desmethylclobazam did not change significantly from baseline. The authors suggest a clobazam dose reduction of 70% to 74% when cenobamate is started.
- Related lesson: 4.1 Phase 1 and phase 2 metabolism
Carbonyl Reductase 1 regulates prednisolone clearance and modifies its adverse effect profile
In 30 healthy men who took prednisolone 20 mg daily for one week, 20β-reduced metabolites were major contributors to prednisolone clearance. In cells, carbonyl reductase 1 (CBR-1) formed these metabolites, and in the volunteers a higher level of 20β-dihydro-prednisone was associated with better glucose disposal and higher osteocalcin.
- Related lesson: 4.4 Genes and metabolism
Pharmacokinetics of Metoprolol in Cisgender Males, Cisgender Females, and Transgender Women Receiving Gender-Affirming Hormone Therapy: An Exploratory Pilot Study
Nine volunteers took one 100 mg oral dose of metoprolol, and the mean AUC was 2550, 2142 and 1522 ng·h/mL in cisgender men, cisgender women and transgender women on hormone therapy. With three people per group and no CYP2D6 genotyping, the authors state that the differences cannot be attributed to sex, gender or hormone therapy.
- Related lesson: 4.4 Genes and metabolism
Distribution of ABCB1 Genetic Variants and their Association with Moxifloxacin Pharmacokinetics in Hospitalized Patients with Acute Exacerbation of COPD
In 30 patients with an exacerbation of COPD who received intravenous moxifloxacin 400 mg daily, heterozygous carriers of the ABCB1 c.1236C>T variant had a mean AUC of 56.24 mg·h/L, and wild-type carriers had 37.57 mg·h/L. The authors state that the sample is small and that larger studies are necessary.
- Related lesson: 6.6 Noncompartmental analysis and population PK
Population pharmacokinetics of piperacillin based on multicenter data to support model-informed precision dosing in critically ill women
A population pharmacokinetic model of piperacillin from 923 samples of 165 critically ill women has two compartments, and its clearance depends on renal function (Cockcroft-Gault), procalcitonin and serum albumin. Bayesian forecasting from one prior sample reduced the median absolute prediction error from below 33.4% to below 19.1%.
- Related lesson: 7.1 In vitro ADME assays
Impact of nonspecific binding to membrane vesicles on unbound IC50 estimation for P-glycoprotein and breast cancer resistance protein inhibitors and implications for drug-drug interaction risk assessment
In vesicle assays of P-gp and BCRP inhibition, nonspecific binding of the inhibitor to the vesicles lowered its free concentration and shifted the IC50 to higher values, most for highly bound compounds such as itraconazole and dronedarone. Binding to microsomes correlated with binding to vesicles (r = 0.965), so microsomal binding can be used to calculate the unbound IC50 that the ICH M12 guidance recommends.
- Related lesson: 7.1 In vitro ADME assays
How Subtle Molecular Differences in the Morphinan Opioid Antagonists Affect Their Physicochemical and In Vitro ADME Properties
Naloxone, naltrexone and nalmefene bind the μ-opioid receptor with similar affinity but have different pharmacokinetics. The study measured their physicochemical properties, PAMPA-BBB permeability and in vitro metabolic stability, and relates the differences to the head group and the C6 group of each molecule.
- Related lesson: 7.4 PBPK models
Toward a Platform PBPK Model to Characterize the Plasma and Tissue Disposition of Unconjugated Antisense Oligonucleotides and GalNAc-Conjugated Small Interfering RNAs in Preclinical Species and Human
A PBPK model with 11 tissue compartments and endosomal trafficking describes the plasma and tissue concentrations of unconjugated antisense oligonucleotides and GalNAc-conjugated siRNAs in mice, rats, monkeys and humans. In the sensitivity analysis, endocytosis and the rate of degradation had the largest effect on disposition.