Background: This study characterized steady-state indinavir (IDV) pharmacokinetics in CSF and plasma among adults with HIV-1 infection receiving concomitant low-dose ritonavir (RTV).

Methods: 7 antiretroviral-naïve subjects received IDV (800-mg q12-h), RTV (100-mg q12-h), d4T and 3TC for 2 weeks. In each patient, CSF was collected by indwelling lumbar catheter on day 14 at 10 precise time points over 12 hours. Plasma was collected simultaneously. IDV was quantified by LC-MS-MS, and free IDV by ultrafiltration.

 

Results: Free Indinavir Concentrations (mean ± SD):

	AUC0-12hr (nM hr)	Cmax (nM)	C12h (nM)
Plasma	38,829 ± 15,124	7,521 ± 1,580	763 ± 820
CSF	6,578 ± 2473	811 ± 363	345 ± 202
CSF:Plasma	17.8% ± 7.2%	10.9% ± 4.9%	64.6% ± 36.6%

 

Free IDV fraction in CSF was 99% ± 1%, and in plasma was 56% ± 4%. IDV exceeded 150 nM in CSF during the entire dosing interval in every subject.

Conclusions: Low-dose RTV increased free IDV AUC in CSF 3-fold without affecting CSF:plasma AUC ratio (vs IDV 800 q8h without RTV. Free IDV level in CSF exceeded the IC₉₅ of wild-type HIV-1 (100 nM) at all times in every patient. Low-dose RTV enhances IDV disposition into CSF primarily by increasing IDV plasma levels, but may also involve P-glycoprotein inhibition.