Therapeutic drug monitoring of darunavir/ritonavir in pregnancy.

BACKGROUND: Physiological changes during pregnancy can have a significant impact on antiretroviral pharmacokinetics (PK), which may result in reduced drug efficacy. Here we describe the PK of darunavir/ritonavir (DRV/r) 800/100 once daily in a cohort of pregnant women undergoing routine therapeutic drug monitoring (TDM) as well as transplacental passage of DRV by measuring and comparing cord blood and maternal blood samples at delivery. METHODS: Pregnant HIV-positive women received DRV/r as part of routine pre-natal care. Demographic and clinical data were collected. DRV plasma concentrations [DRV] were determined in the first (T1), second (T2) and third (T3) trimester and at postpartum (PP). The target concentration was 550 ng/ml. Where possible, paired maternal and cord blood samples were taken at delivery. RESULTS: A total of 33 women were enrolled. Samples were taken 14-20 h post-dose and measured concentrations were extrapolated to 24 h post-dose. At the time nearest to delivery, all but four had undetectable plasma viral loads (pVL). [DRV] were determined in 1 (T1); 14 (T2); 32 (T3) and 29 (PP). 1 sample was <550 ng/ml at T2, 6 at T3 and 3 at PP. [DRV] were significantly lower at T2/T3 relative to PP. CONCLUSIONS: [DRV] in T2 and T3 were 36-55% when compared with PP. However, DRV PK in pregnancy were not associated with a lack of virological suppression at delivery as of the 33 patients enrolled in this study, 31 had no HIV transmission from mother to child. Data regarding two candidates were not available as they delivered in a separate health-care facility.

Darunavir pharmacokinetics throughout pregnancy and postpartum.

INTRODUCTION: Antiretroviral therapy is recommended during pregnancy for prevention of mother-to-child transmission (MTCT) of HIV. Physiological changes during pregnancy are known to affect the pharmacokinetics (PK) of protease inhibitors (PIs), leading to lower exposures in pregnant women. Here we examine the PK of DRV/r 800/100 mg once daily (OD) over the course of pregnancy and postpartum (PP). MATERIAL AND METHODS: In this prospective open-labelled study, HIV-positive pregnant women receiving darunavir/ritonavir as part of their routine maternity care were enrolled. DRV plasma trough concentrations [DRV] were determined in the first (T1) and/or second (T2) and/or third (T3) trimester and PP using a validated HPLC-MS/MS methodology (Lab21, Cambridge UK). Where possible paired maternal and cord blood samples were taken at delivery. RESULTS: To date 20 women (12 black African, 8 Caucasian) have been enrolled. Median (range) baseline CD4 count was 338 cells/µL (108-715), and median baseline plasma viral load was 555 copies/mL (<40-8,188,943). All but 2 women were virally suppressed at time of delivery (114 and 176 copies/mL; 1 sub-therapeutic at T3) and median CD4 count was 410 cells/µL (92-947). There were 20 live births, all term deliveries and there were no cases of MTCT. [DRV] (geometric mean; 95% CI) was 3790 ng/mL at T1 (n=1); 1288 ng/mL (663-1913) at T2 (n=9); 1086 ng/mL (745-1428) at T3 (n=18, 1 undetectable) and 2324 ng/mL (1369-3279) at PP (n=14, 1 undetectable). There was no significant difference in [DRV] between T2 and PP (p=0.158); however, there was between T3 and PP (p=0.021). Nineteen of twenty (95%) and 16 of 20 (80%) women achieved [DRV] above the estimated MEC for WT (55 ng/mL) and PI resistant HIV-1 (550 ng/mL) throughout pregnancy. Maternal and cord [DRV] were available for 10 mother-baby pairs. Mean maternal [DRV] at delivery was 2235 ng/mL (±1557 ng/mL), while mean cord [DRV] was 337 ng/mL (±217 ng/mL). The median cord to maternal blood ratio (C/M) was 0.11 (0.06-0.49). CONCLUSIONS: In most cases examined, DRV/r 800/100 mg once daily was effective at achieving adequate therapeutic drug levels (>550 ng/ml) during pregnancy. However, reduced DRV plasma concentrations in the second/third trimesters highlights the need for TDM in this population and warrants further study of pregnancy-associated changes in DRV pharmacokinetics. The low C/M ratios reported here are consistent with previous reports [1] and suggest low transplacental transfer of DRV.