Pharmacogenetics of pregnancy‐induced changes in efavirenz pharmacokinetics

Olagunju, Adeniyi; Bolaji, Oluseye O.; Amara, Alieu; Else, LJ; Okafor, O; Adejuyigbe, Ebunoluwa A.; Oyigboja, J; Back, David; Khoo, Saye; Owen, Andrew

doi:10.1002/cpt.43

Cited by 42 publications

(36 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies suggest that the activity of CYP2B6 primarily affects the OHBUP levels, but not BUP (Zhu et al, 2012;Benowitz et al, 2013;Høiseth et al, 2015). The pregnancy-induced upregulation of CYP2B6 has been suggested based on in vitro and in vivo studies (Anderson, 2005;Olagunju et al, 2015). However, in our study, we did not observe any significant changes in the OHBUP/BUP metabolic ratio and OHBUP AUC ss in pregnancy as compared with the nonpregnant state.…”

Section: Discussioncontrasting

confidence: 80%

“…Furthermore, in vitro studies suggest the upregulation of hepatic CYP2B6 and downregulation of CYP2C19 by increased production of progestational hormones (Anderson, 2005;Mwinyi et al, 2010;Dickmann and Isoherranen, 2013). These in vitro findings were corroborated by observations in vivo: clearance of CYP2B6 substrates, namely methadone and efavirenz, was higher in pregnancy (Wolff et al, 2005;Olagunju et al, 2015), whereas clearance of the CYP2C19 substrate proguanil was decreased (McGready et al, 2003).…”

Section: Introductionmentioning

confidence: 61%

See 1 more Smart Citation

Pharmacokinetics of Bupropion and Its Pharmacologically Active Metabolites in Pregnancy

Fokina

Rytting

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Bupropion sustained release is used to promote smoking cessation in males and nonpregnant females. However, its efficacy as a smoking cessation aid during pregnancy is not reported. The pregnancyassociated changes in maternal physiology may alter the pharmacokinetics and pharmacodynamics of bupropion and consequently its efficacy in pregnant smokers. Therefore, the aims of this study were to determine the steady-state pharmacokinetics of bupropion during pregnancy and the effect of functional genetic variants of CYP2B6 and CYP2C19 on bupropion pharmacokinetics in pregnant women. Plasma and urine concentrations of bupropion and its metabolites hydroxybupropion (OHBUP), threohydrobupropion, and erythrohydrobupropion were determined by liquid chromatography-mass spectrometry. Subjects were genotyped for five nonsynonymous single-nucleotide polymorphisms that result in seven CYP2B6 alleles, namely *2, *3, *4, *5, *6, *7, and *9, and for CYP2C19 variants *2, *3, and *17. The present study reports that the isoform-specific effect of pregnancy on bupropion-metabolizing enzymes along with the increase of renal elimination of the drug could collectively result in a slight decrease in exposure to bupropion in pregnancy. In contrast, pregnancy-induced increase in CYP2B6-catalyzed bupropion hydroxylation did not impact the plasma levels of OHBUP, probably due to a higher rate of OHBUP glucuronidation, and renal elimination associated with pregnancy. Therefore, exposure to OHBUP, a pharmacologically active metabolite of the bupropion, appears to be similar to that of the nonpregnant state. The predicted metabolic phenotypes of CYP2B6*6 and variant alleles of CYP2C19 in pregnancy are similar to those in the nonpregnant state.

show abstract

Section: Discussioncontrasting

confidence: 80%

Section: Introductionmentioning

confidence: 61%

Pharmacokinetics of Bupropion and Its Pharmacologically Active Metabolites in Pregnancy

Fokina

Rytting

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…[19] In other studies, efavirenz clearance was increased during pregnancy, risk of low trough concentration increased especially in women who were extensive CYP2B6 metabolizers, and exposure decreased. [25,26] These differences may be explained by host genetic polymorphisms in CYP2B6. Efavirenz AUC, C max and C min decreased in women with CYP2B6 516GG genotype, AUC and C max decreased in women with CYP2B6 516TT genotype, and no apparent changes were seen in women with CYP2B6 516GG genotype during pregnancy compared to postpartum.…”

Section: Discussionmentioning

confidence: 99%

“…Efavirenz AUC, C max and C min decreased in women with CYP2B6 516GG genotype, AUC and C max decreased in women with CYP2B6 516TT genotype, and no apparent changes were seen in women with CYP2B6 516GG genotype during pregnancy compared to postpartum. [26 Surprisingly, etravirine exposure is increased during pregnancy compared to postpartum, but metabolism of etravirine is more complex and involves multiple CYP pathways. [20,21] Etravirine is primarily metabolized by CYP2C19 and during pregnancy CYP2C19 expression and activity are decreased.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women

Tran

Best

Stek

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

View full text Add to dashboard Cite

Background Rilpivirine pharmacokinetics are defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. Methods IMPAACT P1026s is a multicenter, non-blinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive PK sampling was performed at steady state during the second trimester, third trimester and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL. Results Median (range) AUC0–24 were 1969 (867–4987, n=15), 1669 (556–4312, n=28) and 2387 (188–6736, n=28) ng*hr/mL in the second trimester, third trimester and postpartum, respectively (p<0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37–225, n=17), 56 (<10–181, n=30), and 81 (<10–299, n=28) ng/mL (p<0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.4–0.8, n=9). Delivery HIV-1 RNA was ≤ 50 copies/mL in 70% and ≤ 400 copies/mL in 90% of women. Cmin were significantly lower at 14 visits with detectable HIV-1 RNA compared to 62 visits with undetectable HIV-1 RNA, 30 (<10 – 93) versus 63 (15 – 199) ng/mL (p=0.0004). Cmin was below the protein-binding adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10%). Conclusions Rilpivirine exposure is lower during pregnancy compared to postpartum, and highly variable. Ninety percent of women had minimum concentrations above the protein-binding adjusted EC90 for rilpivirine.

show abstract

“…Prescribing pregnant HIV‐infected women with combination antiretroviral treatment is critical for the prevention of mother‐to‐child transmission of the virus, and adequate maternal exposure to antiretroviral drugs is required for the maximal reduction of viral load and the reduced risk of viral transmission. Reductions in maternal exposure to these drugs during pregnancy may lead to subtherapeutic levels, as shown for a number of drugs, including atazanavir, indinavir, ritonavir, darunavir, and efavirenz, eventually leading to virologic failure and/or drug resistance. Historically, for several antiviral drugs (e.g., tenofovir, darunavir, and efavirenz) there has been a significant lag time, ranging from 8–15 years between the initial US Food and Drug Administration (FDA) approval of a drug and the time when pregnancy data first became available (personal communications with Drs Stein Schalkwijk and Angela Colbers, Radboud University Medical Center, Nijmegen, The Netherlands).…”

Section: Current Status and Need For Clinical Studies In Pregnant Womenmentioning

confidence: 99%

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

Greupink

Abduljalil

2018

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

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.

show abstract

Pharmacogenetics of pregnancy‐induced changes in efavirenz pharmacokinetics

Cited by 42 publications

References 41 publications

Pharmacokinetics of Bupropion and Its Pharmacologically Active Metabolites in Pregnancy

Pharmacokinetics of Bupropion and Its Pharmacologically Active Metabolites in Pregnancy

Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women

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

Contact Info

Product

Resources

About