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A Comparison of the Pharmacokinetics of Efavirenz During Pregnancy and Postpartum
Stein Schalkwijk1; Brookie M. Best2; Angela Colbers1; Alice Stek3; Jiajia Wang4; David Hawkins5; Mark Mirochnick6; David M. Burger1; for the The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1026s Protocol Team, and the Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-infected Pregnant Women (PANNA) Study Network
1Radboud Univ Med Cntr, Nijmegen, Netherlands;2Univ of California San Diego, San Diego, CA, USA;3Univ of Southern California, Los Angeles, CA, USA;4Harvard Sch of PH, Boston, MA, USA;5Chelsea and Westminster Hosp NHS Fndn Trust, London, UK;6Boston Univ Sch of Med, Boston, MA, USA
Efavirenz (EFV) 600mg is currently recommended by WHO as a first-line antiretroviral agent in HIV infected adults. A dose reduction to 400mg EFV has been proposed because of concerns regarding toxicitity. EFV is widely used during pregnancy in those countries where HIV infection is most common. Pregnancy can reduce exposure to antiretroviral agents with a corresponding risk of poor maternal virologic control and PMTCT. Pharmacokinetics (PK) of EFV 600 mg have been previously studied in pregnancy with contradictory results. The aim of this multinetwork study was to further investigate the PK of EFV 600 mg in pregnant women.
HIV-infected pregnant women treated with EFV 600 mg once daily were recruited by the P1026s network (N=10) and PANNA network (N=13). Intensive PK profiles were obtained during 2nd (2T) and 3rd trimester (3T) and at least two weeks postpartum (PP). 2T and 3T PK parameters were compared with PP. Where possible cord blood and maternal delivery blood samples were obtained.
Seven, 19 and 22 women completed 2T, 3T, and PP PK evaluations. Median (range) age was 33 (20-40) years. 21 subjects were Black, 2 mixed race.
The geometric means (GM) (95% CI) for AUC0-24h, Cmax and Cmin in 3T were 60 (49-74) mg*h/L, 4.6 (3.7-5.5) mg/L and 1.8 (1.4-2.3) mg/L, respectively. The GM during PP for AUC0-24h, Cmax and Cmin were 63 (50-80) mg*h/L, 4.3 (3.4-5.3) mg/L and 1.9 (1.4-2.6) mg/L, respectively. When comparing 3T to PP (N=19), GM ratios (90% CI) were 1.01 (0.92-1.10), 1.11 (0.94-1.29), and 0.97 (0.82-1.16) for AUC0-24h, Cmax, and Cmin. Similar results were found when comparing 2T to PP (N=5). Two patients had a Cmin below the suggested threshold of 1.0 mg/L during 3T, but not PP. One patient had a Cmin below 1.0 mg/L only PP. Three patients used concomitant rifampicin, but no obvious deviations were observed and Cmin levels were >1.0 mg/L.
Median (range) gestational age at delivery was 39 wks(33-42); birth weight was 3310 (1875-4150) gm. All of the children for whom HIV-infection status was available were not infected as of the last HIV test. The median (range) ratio of cord to maternal concentrations (n=4), was 0.81 (0.65-0.95).
No significant effects of pregnancy on EFV PK parameters were observed and EFV 600mg led to adequate exposure during pregnancy. The absence of a significant pregnancy-related effect on EFV PK in this study suggests that a prospective evaluation in pregnant women of the proposed EFV dose reduction to 400mg is warranted.