RAL-KAL: PHARMACOKINETICS OF COADMINISTERED RALTEGRAVIR AND LOPINAVIR-RITONAVIR IN HEALTHY ADULTS
Reported by Jules Levin
IAC, Mexico City, Aug 3-8, 2008
Frank Rhame, University of Minnesota, Abbott Northwestern Hospital;
Mary Long, University of Alabama at Birmingham;
Edward Acosta, University of Alabama at Birmingham
RAL was well tolerated
- No unexpected AEs were noted to RAL or KAL
The %CV on AUC0-12h, Cmax, and C12h for RAL alone were 66%, 84%, and 41%, respectively
- Similar variability was seen when dosed with KAL
RAL C12h decreased 30% in the presence of KAL
-- One subject (8.3%) in the RAL+KAL arm had a measured RAL trough of
10.9 ng/mL, which is below the estimated IC95 of 33nM (14.6 ng/ml)
--The significance of this in the context of multiple drug therapy is unclear
In general, RAL and KAL can be co-administered without dose adjustments
--Applicability in all contexts (eg, HIV+ persons) uncertain
-- Glucuronide metabolites not measured
-- The interpretation of drug-drug interactions requires well-defined
exposure-response data and analyses in all relevant settings
-- Randomized, large, prospective clinical studies are lacking
Background: RAL, an anti-HIV integrase inhibitor, is metabolized by UGT1A1 glucuronidation. It is not an inhibitor or an inducer of UGT1A1 nor a substrate for CYP isoforms, but is a substrate for P-glycoprotein (PgP). Atazanavir increases while tipranavir/ ritonavir decreases RAL concentrations. We determined the PK interaction of RAL and KAL.
Methods: 15 healthy subjects entered a sequential study: Period 1, 400 mg RAL bid for 4 days; Period 2, 2 KAL tabs bid for 10 days; Period 3, both for 4 days. 11 samples were obtained over 12 hours on the last day of each period. RAL concentrations were determined by liquid chromatography-mass spectrometry-mass spectrometry. Lopinavir and ritonavir concentrations were determined by high performance liquid chromatography. PK parameter estimates were determined using non-compartmental methods. Nonparametric statistics were used.
3 subjects did not complete the protocol: 1 became pregnant, 1 had a positive tuberculin skin, one had grade 2 nausea and vomiting during Period 2. 2 subjects in Period 1 and 7 subjects in Period 2 had grade 1 clinical toxicity. No laboratory toxicities occurred. RAL, LPV, and RTV PK were similar to previously reported data.
RAL C12h from Period 1 vs. Period 3 showed a decrease (geometric mean, 49.4 vs. 34.4 ng/mL, respectively, p=0.02).
RAL geometric mean Cmax and AUC12 (%CV) from Periods 1 and 3 were: 1698 (84%) ng/mL and 5.3 (67%) h*mg/L vs. 1687 (90%) ng/mL and 5.4 (67%) h*mg/L, respectively. LPV Cmax, C12h, and AUC12 from Period 3 were: 9473 (24%) ng/mL, 2604 (63%) ng/mL, and 74.5 (32%) h*mg/L. LPV and RTV parameters were similar across periods.
RAL was well tolerated.
RAL C12h decreased 30% in the presence of LPV/r, but sufficient exposure remained relative to an estimated IC95 of 33 nM (15 ng/mL).
RAL and KAL can be co-administered without dose adjustment.
15 Healthy, HIV- subjects recruited and studied at Prism Research,
Three phases, in immediate succession
- Phase 1: RAL 400 bid for 7 doses
- Phase 2: KAL tabs 2 bid for 19 doses
- Phase 3: Both bid for 7 doses
12 hour samples (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12)
at the last dose of each phase
· Analyte determinations were performed at the UAB Antiviral Pharmacology
- validated LC/MS/MS method; Linear range from 1-3000 ng/mL
· Lopinavir, ritonavir
- validated HPLC-UV method; Linear range from 25-20,000 ng/mL
· PK parameters were estimated using non-compartmental methods (WinNonlin v5.2)
· Nonparametric statistics and geometric mean ratios (GMR) with 90% confidence intervals were used to identify differences in PK parameters between treatment arms
3 subjects did not complete the study
-- 1 became pregnant
-- 1 had Gr 2 nausea in Phase 2 (KAL)
-- 1 appeared for 24 hour inpt stay with a pos TST and we couldnŐt get a
There was no other lab or clinical AE at Gr 2-4 and none at Gr 1 probably or
definitely attributed to RAL.