Once-daily darunavir (DRV) used in routine clinical care produces trough DRV drug concentrations in excess of 30× the protein-corrected (PC) EC50 for wild-type HIV

Abstract

Background: In clinical practice measured drug concentrations often exhibit significant differences to those published in clinical trials. This can impact on virological efficacy and drug toxicity. The aim of this study is to assess DRV concentrations achieved in a cohort of HIV-positive individuals using a non-standard dose of DRV 900 mg OD with RTV 100 mg OD. Methods: Sixty-nine HIV-positive patients with no DRV resistance-associated mutations were commenced on antiretroviral therapy (ART) regimens with DRV/RTV 900/100 mg OD and were followed prospectively. Trough [DRV] (C24) actual and predicted were recorded and compared with published protein-corrected (PC) EC50 values for WT HIV (55 ng/mL) and (PC) EC50 for resistant HIV (550 ng/mL). Results: Fifteen patients started DRV/RTV as their first PI-based regimen. Others changed for: ART simplification/move to OD ART (n = 17), gastrointestinal side effects (n = 15), low level viraemia (n = 6), jaundice (n = 6), lipid abnormalities (n = 6) and perceived potency (n = 5). Regimens changed from were: LPV/r(n = 25), ATV/r (n = 20), FAPV/r (n = 2), double-boosted PI (n = 7). Twenty-nine patients provided actual trough samples (23-26.5 hrs post drug) (median 24 hour). The median trough [DRV] was 1593 ng/mL (range 413582); this is 30x the PCEC50 for WT HIV. A further 21 patients provided blood samples a median of 15 hours (12.5-19 hour) post drug ingestion. Using a T1/2 of 15 hrs the projected C24 [DRV] was 2026 ng/mL (772-4558) representing 37x the PCEC50 for WT HIV. Furthermore, 50/51 levels were above the PCEC50 for resistant HIV. No patients have exhibited virological failure to date. There was no incidence of rash and only one grade 1 LFT abnormality. Multivariate analysis revealed no significant association of trough [DRV] with age, gender or ethnicity. Conclusions: Once daily Darunavir used in routine clinical care produces trough DRV drug concentrations in excess of 30x the PCEC50 for WT HIV. This is in keeping with data from randomised controlled trials.