Darunavir pharmacokinetics in pregnancy and postpartum
Polly Clayden, HIV i-Base
Data presented at the 2014 HIV Drug Therapy Glasgow Congress found once-daily darunavir/ritonavir (DRV/r) 800/100 mg achieved adequate therapeutic drug levels during pregnancy in most cases.
John Lambert showed findings on behalf of colleagues from Mater and Rotunda Hospitals, University College Dublin, and Department of Pharmacology and Therapeutics, University of Liverpool from a prospective, open-label study of pregnant, HIV positive women receiving DRV/r as part of their routine care.
The investigators looked at pharmacokinetics (PK) of DRV/r 800/100 mg once daily during pregnancy and postpartum.
DRV plasma trough concentrations were determined in the first and/or second and/or third trimester and postpartum using validated HPLC-MS/MS (lower limit of quantification of 78 ng/mL). Where possible paired maternal and cord blood samples were taken at delivery.
Twenty-three women (14 black African, 9 white) were enrolled in the study. At baseline their median CD4 count was 354 cells/mm3 and viral load was 555 copies/mL. All but two women were <50 copies/mL (114 and 176 copies/mL) at delivery. About half the women started ART in pregnancy at a median gestational age of 19 weeks; the majority (78%) received tenofovir/emtricitibine backbone ART.
There were 23 live births and no cases of vertical transmission.
The investigators found the DRV plasma concentrations were 47% and 52% lower in the second and third trimesters compared with postpartum, p<0.02. All accept one woman achieved minimum DRV trough concentrations for wild type (55 ng/mL) throughout pregnancy. All except for four women in the third trimester achieved minimum trough concentrations for protease inhibitor resistant virus (550 ng/mL).
Geometric mean DRV plasma concentration was: 3790 ng/mL (n=1), 1323 ng/mL (95% CI 864 – 1782), 1195 ng/mL (95% CI 914 – 1475) and 2511 ng/mL (95% CI 1705 – 3317) in the first, second and third trimesters and postpartum respectively. Second trimester vs post partum, p=0.02, and third trimester vs post partum, p=0.003.
Maternal and cord DRV concentrations were available for 10 mother/baby pairs. Mean maternal DRV concentration at the time of delivery was 1668 ng/mL (range 607 – 5528), and mean cord DRV was 254 ng/mL (<LLQ – 745). The median cord to maternal blood ratio was 0.11 (0.06 – 0.49).
Dr Lambert concluded that in most cases examined, DRV/r 800/100 mg once daily achieved adequate therapeutic drug levels during pregnancy. Reduced DRV concentrations in the second and third trimesters suggest TDM should be used in this population. He commented that the case for switching to twice daily dosing – as recommended by BHIVA and other guidelines – might not outweigh the advantages of continued once daily dosing. Although twice daily might be necessary for women with resistant virus or who start treatment in late pregnancy.
Although total DRV exposure decreases during pregnancy, studies have shown no significant changes in unbound DRV concentration compared with postpartum – there are limited data to characterise this for the currently available PIs and a protein binding effect has only been studied in lopinavir. Lambert et al plan to examine the effect of pregnancy and protein binding with DRV in their cohort.
For dosing DRV/r, BHIVA pregnancy guidelines currently recommend: “Consider twice-daily darunavir if initiating darunavir- based ART or if known resistance.” (Grading2C) The guidelines also note that the clinical relevance of pharmacokinetic studies such as the one above has yet to be determined. When a woman conceives on DRV/r-based ART and has a fully suppressed viral load on a once-daily regimen, the guidelines suggest this is continued. A more cautious approach using twice-daily DRV/r can be considered if starting ART in pregnancy with DRV/r or when there is known protease inhibitor resistance.
The guideline writing group note that although the pharmacokinetic data are consistent across studies, the virological impact during pregnancy and post partum are unknown. Such outcome data are needed.
Lambert J et al. Darunavir pharmacokinetics throughout pregnancy and postpartum. HIV Drug Therapy Glasgow Congress, 2-6 November 2014. Oral abstract O132. Journal of the International AIDS Society 2014, 17(Suppl 3):19485