Determinants of darunavir cerebrospinal fluid concentrations: impact of once-daily dosing and pharmacogenetics

Objectives: To compare cerebrospinal fluid (CSF) darunavir and ritonavir concentrations in patients receiving darunavir/ritonavir 800/100mg once daily or 600/100mg twice daily. To determine the influence of single-nucleotide polymorphisms in the genes encoding for blood–brain barrier transporters (ABCB1 3435 C>T, ABCB1 1236 C>T, ABCB1 2677G>T, SLCO1A2 38 A>G, SLCO1A2 516 A>C, ABCC2 -24 G>A) on darunavir and ritonavir penetration into CSF. Design: Comparative pharmacokinetics study in patients. Methods: Plasma and CSF darunavir and ritonavir concentrations (2–26 h after drug intake) were determined by a validated HPLC coupled with mass spectrometry method in adults on darunavir-based combination antiretroviral therapy undergoing a lumbar puncture. Results: HIV-infected patients on once-daily darunavir/ritonavir had significantly lower CSF darunavir trough concentrations and CSF-to-plasma ratios than patients on darunavir/ritonavir twice-daily (10.7 versus 38.2 ng/ml and 0.32 versus 0.90%; P<0.05). No significant effect of single-nucleotide polymorphisms in the genes encoding for blood–brain barrier transporters was noted apart from slightly higher CSF darunavir penetration in patients carrying OATP1A2 uncommon variants. Conclusions: This is the first study to compare darunavir CSF concentrations in patients taking the once-daily or the twice-daily dosage: our data show that darunavir and ritonavir dosing significantly affects not only CSF concentrations but also the extent of drug penetration into the CSF. Furthermore a minority of patients in the once-daily arm presented very low CSF concentration of potential concern for HIV control in the central nervous system. The relative importance of pharmacogenetics in influencing CSF darunavir pharmacokinetics deserves further clinical investigation.