568
Effect of Famotidine 20- and 40-mg Dosing Regimens on the Bioavailability of Atazanavir with Ritonavir in Combination with Tenofovir in Healthy Subjects
Sangeeta Agarwala*, A Persson, T Eley, M Child, D Filoramo, T Li, X Xu, and R Bertz
Bristol-Myers Squibb Pharma Res Inst, Princeton, NJ, US
Background: Previously, a reduction of 18 to 28% in atazanavir
(ATV) exposures was noted when the H2-receptor antagonist,
famotidine (FAM) 40 mg every 12 hours was administered with ATV/ritonavir (RTV)
300/100 mg in healthy subjects; the effect of lower doses of FAM and
combination with tenofovir (TDF) have not been studied. TDF decreases ATV
exposures when coadministered with ATV/RTV by ~25 to 30%. The objective was to
evaluate dosing strategies for FAM to maintain ATV exposures when
coadministered with RTV and TDF.
Methods: Healthy subjects (n
= 40) received 300/100/300 mg ATV/RTV/TDF once daily for 10 days (Trt A). Subjects were then randomized into 2 cohorts (n = 20). Cohort 1 received FAM 20 mg every
12 hours, morning FAM was co-administered with ATV/RTV/TDF for 7 days (Trt B), followed by
FAM 20 mg every 12 hours, morning FAM was given 2 hours after
ATV/RTV/TDF for 7 days (Trt C). Cohort 2 received FAM
40 mg every afternoon, 12 h from ATV/RTV/TDF for 7 days (Trt
D), followed by FAM 40 mg every 12 hours temporally separated as in Trt C (Trt
E). Intensive pharmacokinetic was evaluated on days 10, 17, and 24. In all Trt,
ATV/RTV/TDF was administered in the AM with a light meal. Adjusted geometric
mean ratios (GMR) and 90% confidence intervals (CI) for ATV pharmacokinetics
were estimated by general linear mixed effects models with Trt A as the
reference.
Results: GMR of ATV pharmacokinetics for each of Trt B-E relative to
Trt A with 90% CI are shown: Similar ATV exposures were noted for Trt B, C,
and D when compared to Trt A; 90%CI were within 0.80 to 1.25 for ATV Cmax
in Trt B, C, and D and AUC in Trt B and C. AUC in Trt D fell just below 0.80. Cmin was 18 to 23% lower for Trt B, C, and D. In
contrast, decreases in ATV Cmax, AUC, and Cmin
of 26%, 21%, and 28% were noted with Trt E. RTV and TDF exposures were similar
with FAM. No unexpected adverse events were noted.
|
Parameter
|
Trt
|
GMR (90%CI)
|
|
Cmax
(ng/mL)
|
B
C
D
E
|
0.91 (0.84, 0.99)
0.96 (0.86, 1.06)
0.89 (0.81, 0.97)
0.74 (0.66, 0.84)
|
|
AUC(TAU)
(ng·h/mL)
|
B
C
D
E
|
0.90 (0.82, 0.98)
0.96 (0.88, 1.04)
0.88 (0.798, 0.96)
0.79 (0.70, 0.88)
|
|
Cmin
(ng/mL)
|
B
C
D
E
|
0.81 (0.69, 0.94)
0.82 (0.69, 0.98)
0.77 (0.63, 0.93)
0.72 (0.63, 0.83)
|
Conclusions: This study demonstrates several possible ways to administer
ATV/RTV with both TDF and FAM. Relative to ATV/RTV 300/100 mg + TDF, ATV
exposures were similar when FAM was given as 20 mg twice daily simultaneously
administered or temporally separated, or temporally separated as 40 mg every
afternoon.
|
