18, * on behalf of the participants of the WHO-IMPAACT workshop on "Approaches to Optimize and Accelerate Pharmacokinetic Studies in Pregnant and Lactating Women" † Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network and the World Health Organization (WHO)convened Pediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low-income and middleincome countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy pharmacokinetic/pharmacodynamic (PK/PD) studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical. BACKGROUND Pregnancy is associated with profound physiologic, immunologic, structural, and inflammatory changes. 1 These dynamic changes occur in the maternal and feto-placental units during pregnancy, and significantly influence the pharmacokinetic (PK) processes of drug absorption, 2 distribution, 3,4 metabolism, 1,5 and excretion. 6 For women living with HIV, altered pharmacokinetics during pregnancy can often result in lower antiretroviral (ARV) drug exposures, 7-9 possibly increasing the risk of treatment failure, 10 maternal HIV disease progression, perinatal transmission, drug resistance, 11 and maternal death. 11 Some guidelines recommend dose adaptation of certain ARVs in pregnancy because of lower drug exposures (lopinavir/ritonavir; darunavir/ritonavir). 12

Most breastfed infants are exposed to <10% of the weight-adjusted therapeutic pediatric dose, the safety threshold for exposure to maternal drugs from breast milk.

AimsUsing a model‐based approach, the efavirenz steady‐state pharmacokinetics in African children is characterized, quantifying demographic and genotypic effects on the drug's disposition. Simulations are also conducted allowing prediction of optimized doses of efavirenz in this population.MethodsWe modelled the steady‐state population pharmacokinetics of efavirenz in Ugandan and Zambian children using nonlinear mixed‐effects modelling. Individual mid‐dose efavirenz concentrations were derived and simulations explored genotype‐based dose optimization strategies.ResultsA two‐compartment model with absorption through transit compartments well described 2086 concentration‐time points in 169 children. The combined effect of single nucleotide polymorphisms (SNPs) 516G>T and 983T>C explained 44.5% and 14.7% of the variability in efavirenz clearance and bioavailability, respectively. The detected frequencies of composite CYP2B6 genotype were 0.33 for 516GG|983TT, 0.35 for 516GT|983TT, 0.06 for 516GG|983TC, 0.18 for 516TT|983TT, 0.07 516GT|983TC and 0.01 for 516GG|983CC. The corresponding estimated clearance rates were 6.94, 4.90, 3.93, 1.92, 1.36, and 0.74 l h−1 for a 15.4 kg child and median (95% CI) observed mid‐dose concentrations 1.55 (0.51–2.94), 2.20 (0.97–4.40), 2.03 (1.19–4.53), 7.55 (2.40–14.74), 7.79 (3.66–24.59) and 18.22 (11.84–22.76) mg l−1, respectively. Simulations showed that wild‐type individuals had exposures at the bottom of therapeutic range, while slower metabolizers were overexposed.ConclusionsDosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C.

Pregnancy-induced physiological changes alter many drugs' pharmacokinetics. We investigated pregnancy-induced changes in efavirenz pharmacokinetics in 25 pregnant and 19 different postpartum women stratified from 211 HIV-positive women in whom a preliminary pharmacogenetic study had been undertaken. Despite significant changes in CL/F during pregnancy (42.6% increase; P = 0.023), median (range) Cmin was 1,000 ng/mL (429-5,190) with no significant change in Cmax (P = 0.072). However, when stratified for CYP2B6 516G>T (rs3745274) genotype, efavirenz AUC0-24 , Cmax and Cmin were 50.6% (P = 0.0013), 17.2% (P = 0.14), and 61.6% (P = 0.0027) lower during pregnancy (n = 8) compared with postpartum (n = 6) in 516G homozygotes, with values of 25,900 ng.h/mL (21,700-32,600), 2,640 ng/mL (1,260-3,490), and 592 ng/mL (429-917), respectively, and CL/F was 100% higher (P = 0.0013). No changes were apparent in CYP2B6 516 heterozygotes (14 pregnant vs. 7 postpartum). The clinical implications of these findings warrant further investigation.

The dried breast milk spot method is simple, robust, accurate and precise, and can be used in settings with limited resources.

The validated assay is now routinely applied to clinical samples measuring DBS EFV for pharmacokinetic analysis. The methodology is robust, accurate, and sensitive.

These methods further extend opportunities for conducting clinical pharmacokinetic studies in nursing mother-infant pairs, especially in resource-limited settings.

Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.