Background 
Women are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy.
Methods and Findings 
Systematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown.
Conclusion 
This systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.

/pdf/pregnancy-associated-changes-in-pharmacokinetics-a-wxd5cgyxtm.pdf

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. CYP2C19 genetic variation impacts the metabolism of many drugs and has been associated with both efficacy and safety issues for several commonly prescribed medications. This GeneFocus provides a comprehensive overview and summary of CYP2C19 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.1973

PharmVar GeneFocus: CYP2D6.

Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naive patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.

https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1002/cpt.156

Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naive HIV-Infected Patients: Results of the ENCORE1 Study

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed

/pdf/drug-dosing-during-pregnancy-opportunities-for-13uvev2wbu.pdf

Drug dosing during pregnancy-opportunities for physiologically based pharmacokinetic models.

The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recognized by the regulatory bodies. Physiologically based pharmacokinetic (PBPK) modeling offers an attractive platform to quantify anticipated changes in the pharmacokinetics (PKs) of drugs during pregnancy. Recent publications applying a pregnancy PBPK module to the prediction of maternal and fetal exposure of drugs are summarized. Future opportunities to use PBPK models to predict breast milk exposure and assess human fetotoxicity risks are presented.

https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.12274

Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

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.

Pharmacogenetics of pregnancy-induced changes in efavirenz pharmacokinetics.

Dried blood spots (DBS) were collected from a total of 34 mother-infant pairs (Figure 1). LC-MS/MS method parameters (%CV): LLOQ, 25ng/ml (11.4); LQC, 100ng/ml (8.3); MQC, 1500ng/ml (6.4); HQC, 3500ng/ml (7.5). Patient demographics are presented in Table 1. EFV concentrations in mothers and infants exhibited wide variability (Table 2). The median infant/maternal EFV concentration ratio was 0.06 (95% CI: 20.05, 0.08). *

Exposure of Breastfed Infants to Maternal Efavirenz from Breast Milk (Abstract #933)

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Pharmacogenetics of pregnancy-induced changes in efavirenz pharmacokinetics.

Exposure of Breastfed Infants to Maternal Efavirenz from Breast Milk (Abstract #933)