Efavirenz, Dolutegravir, and Darunavir: Pharmacokinetics during Pregnancy

Three studies presented at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) explored the pharmacokinetics of antiretrovirals administered during pregnancy. These studies support the use of standard-dose efavirenz, once-daily dolutegravir, and BID ritonavir-boosted darunavir during pregnancy.

Efavirenz

Researchers recruited 34 patients from the IMPAACT P1026s and PANNA networks to examine pharmacokinetics of efavirenz 600 mg in pregnant HIV-infected women. Geometric mean ratios for AUC0-24, Cmax, and Cmin were all close to 1.00 for the 23 women who had available data for both third-trimester and postpartum measurements. Two of 19 patients had Cmin levels below the recommended therapeutic level of 1.0 mg/L during their third trimester. In this study, pregnancy did not significantly alter efavirenz exposure; the finding is consistent with previous studies that found slightly lower efavirenz AUCs during the third trimester but an overall adequate exposure. Collectively, these studies appear to indicate that pregnancy does not have a significant impact on efavirenz pharmacokinetics for most women and dosage adjustment is not typically required.

Dolutegravir

As part of the IMPAACT protocol P1026s, researchers looked at the effect of pregnancy on dolutegravir pharmacokinetics in 22 HIV-infected pregnant women. Data were available for 15 women in the third trimester and for 9 women postpartum who completed intensive PK studies. AUC0-24 were 25-30% lower in the third trimester compared with postpartum (48.7 vs 71.1 mcg*h/mL). In the study, these differences were not statistically significant, and the AUCs were similar to AUC0-24 that are historically seen in nonpregnant individuals (53.6 mcg*h/mL). Dolutegravir Cmin also was lower in the third trimester compared with postpartum (0.86 vs 1.70 mcg/mL) and somewhat lower than in nonpregnant individuals (1.11 mcg/mL). The study authors suggest that dolutegravir does not require dosage adjustment during pregnancy; however, given that Cmin generally was lower in the pregnant study subjects than in the nonpregnant population, strict adherence to the regimen will be important for maintaining adequate dolutegravir levels during pregnancy.

Darunavir/ritonavir

Limited data suggest that once-daily darunavir should be avoided during pregnancy due to low trough concentrations, and current guidelines approve the use of darunavir 600 mg BID, boosted with 100 mg of ritonavir BID. With this BID dosing strategy, total darunavir (active plus protein-bound) AUC0-12 is 17-33% lower in the third trimester compared with postpartum. However, when looking only at unbound (active) darunavir, third-trimester and postpartum AUCs are similar, supporting standard dosing. IMPAACT P1026s examined the effect of using higher doses of darunavir -- 800 mg BID boosted with ritonavir 100 mg BID -- in HIV-infected pregnant women. 18 women completed intensive PK studies, yielding data for 17 women in the third trimester and 15 women postpartum. AUC0-12 levels were 36% lower in the third trimester compared with postpartum when using darunavir 800 mg BID (52.1 vs 80.9 mcg*h/mL). As a comparison reference, the authors displayed AUC data for darunavir 600 mg BID in the third trimester and postpartum (45.9 vs 61.7 mcg*h/mL); there was a small overlap in the interquartile ranges for 600 vs 800 mg BID. Study authors concluded that, in pregnant women, increased darunavir doses did not significantly improve exposure compared with standard BID dosing of darunavir 600 mg/ritonavir 100 mg. It is unclear why the higher doses of darunavir did not improve third-trimester/postpartum exposure ratios. This study did not separately examine unbound darunavir fractions and the study findings might be accounted for by increases in volume of distribution or changes in absorption during pregnancy. Until further studies refute these findings, elucidate the reasons behind for lower exposure, or examine unbound (active) darunavir exposure, it seems prudent to continue using standard 600 mg/100 mg BID dosing of darunavir/ritonavir in pregnant HIV-infected women.

References

  • Schalkwijk S, Best BM, Colbers A, et al. A comparison of the pharmacokinetics of efavirenz during pregnancy and postpartum. In: Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston. Abstract 433.
  • Mulligan N, Best BM, Capparelli E, et al. Dolutegravir pharmacokinetics in HIV-infected pregnant and postpartum women. In: Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston. Abstract 438.
  • Stek A, Best BM, Capparelli E, et. al. Pharmacokinetics of increased dose darunavir during late pregnancy and postpartum. In: Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston. Abstract 775.

 

  • Dr. Cocohoba is Health Sciences Associate Clinical Professor in the Department of Clinical Pharmacy at the UCSF School of Pharmacy. Dr. Cocohoba specializes in HIV/AIDS Ambulatory Care Pharmacy. She serves as the clinical pharmacist responsible for developing and maintaining the treatment adherence program at the Ryan White funded UCSF Womens’ HIV Program (WHP). She also serves as a faculty advisor and research mentor for the UCSF student-run free clinic, the Mabuhay Health Center. Dr. Cocohoba conducts research on pharmacy-based interventions to improve adherence to HIV antiretroviral medicines, antiretroviral therapy concordance with national treatment guidelines, sex-related HIV treatment disparities, and on health of Filipino-Americans.