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  11th International Workshop on Clinical Pharmacology of HIV Therapy
Sorrento, Italy
April 7-9, 2010
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Cell Levels of Once-Daily Raltegravir Adequate in Pilot Study
  11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Daria Hazuda of Merck, in response to this report says:
"Levels in PBMCs are consistent with the free (unbound) fraction which is 10 to 20 percent that of circulating plasma levels. RAL penetrates PBMCs freely as the levels in the PBMCs are in equilibrium with the unbound fraction in the plasma."
Raltegravir levels in peripheral blood mononuclear cells (PBMCs) averaged about one-tenth of plasma levels in 5 HIV-infected men taking the integrase inhibitor at a dose of 800 mg once daily [1]. Still, PBMC trough concentrations of raltegravir remained above the 50% effective concentration for wild-type (nonmutant) HIV, 0.4 ng/mL.
Interest in once-daily raltegravir has grown, partly because pharmacokinetic/pharmacodynamic study did not discern a traditional correlation between viral response and raltegravir concentration in plasma. This lack of a correlation fueled speculation that response to raltegravir may be linked to intracellular levels of the drug rather than to plasma levels.
To gain some insight into raltegravir levels in PBMCs of virologic responders, Jose Molto and colleagues in Barcelona and Liverpool measured plasma and PBMC levels in 5 men who added 800 mg of raltegravir once daily to suppressive lopinavir/ritonavir monotherapy for 10 days. Study participants took raltegravir once each morning without regard to food, until day 10, when they took the integrase inhibitor after fasting. The investigators collected blood samples at dosing on day 10 and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24 hours after dosing.
The 5 men had a median age of 40 years (range 24 to 47) and a median body mass index of 24.4 kg/m(2) (range 18.2 to 25.5). Everyone tolerated raltegravir well and completed the 10-day study.
Time to maximum concentration and raltegravir half-life did not differ in plasma and PBMCs. But raltegravir maximum concentration (Cmax), trough concentration (Ctrough) and area under the curve (AUC) were all significantly lower in PBMCs than in plasma:
· Average Cmax: 2639.6 ng/mL (range 8887.0 to 10,605) in plasma versus 198.5 ng/mL (range 81.7 to 856.9) in PBMCs
· Cmax geometric mean ratio for plasma/PBMCs: 13.30 (range 3.11 to 56.88, P = 0.003)
· Average Ctrough: 89.3 ng/mL (range 51.0 to 200.0) in plasma versus 6.8 ng/mL (range 1.6 to 15.2) in PBMCs
· Ctrough geometric mean ratio for plasma/PBMCs: 13.21 (range 3.94 to 44.27, P = 0.001)
· Average AUC: 12,199.7 ng x h/mL (range 5151.5 to 30,130.0) in plasma versus 908.9 ng x h/mL (range 499.1 to 2188.8) in PBMCs
· AUC geometric mean ratio for plasma/PBMCs: 13.43 (range 5.12 to 35.17, P < 0.001)
Although these pilot study findings indicate that raltegravir penetrates PBMCs poorly, in these men it penetrated cells well enough to sustain a Ctrough above the calculated 0.4 ng/mL needed to suppress wild-type virus.
1. Molto J, Valle M, Back D, et al. Pharmacokinetics of once-daily raltegravir (800 mg) in plasma and PBMCs in HIV-infected patients. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract LB-01.