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Bioequivalence of Pilot Tablet Formulations of Ritonavir to the Marketed Soft Gel Capsule at a Dose of 100 mg
Y Cai1, C Klein1, U Roggatz2, W Roth2, T Jung2, K Fastnacht2, J Morris1, B Freyer-Kern2, B Bernstein1, and George Hanna*1
1Abbott Labs, Abbott Park, IL, US and 2Abbott GmbH & Co KG, Ludwigshafen, Germany
Background: A 100-mg ritonavir
(RTV) tablet formulation is being developed to eliminate the need for
refrigeration. Other formulation objectives include bioequivalence to the
marketed soft gel capsule (SGC), chemical and physical stability over a range
of temperature and humidity conditions, and acceptable size. We assessed the
bioavailability of 3 prototype tablet formulations (form A, B, and C) with
limited stability evaluations administered as a 100-mg dose.
Methods: This
phase 1, open-label, 4-period, randomized, crossover study enrolled 32
HIV-negative healthy adults to receive a single 100-mg dose of 1 of 3 RTV
tablet formulations or SGC 30 minutes after a moderate-fat meal with a washout
of at least 7 days between dosing periods. Serial blood samples were collected
for 36 hours after dosing and plasma concentrations of RTV were determined by a
validated high performance liquid chromatography mass spectrometry/mass
spectrography (HPLC/MS/MS) assay. The
pharmacokinetic parameters of RTV were determined using non-compartmental
methods, including maximum plasma concentration (Cmax), area under
the plasma concentration time curve (AUC) from time 0 to time of last
measurable concentration (AUCt), and AUC extrapolated to infinity
(AUCinf). The bioavailability of tablet formulations relative to SGC
was assessed by the 2 one-sided tests procedure via 90% confidence intervals
(CI).
Results: The 90%CI for
log-transformed RTV Cmax, AUCt, and AUCinf
were contained within the 0.80 to 1.25 range for form A and form B relative to
the SGC. The 90%CI for log-transformed RTV AUCt and AUCinf
were contained within the 0.80 to 1.25 range for form C relative to the SGC.
The RTV Cmax was approximately 20% higher with form C than for the
SGC. All formulations were generally safe and well tolerated.
|
Formulation
|
Pharmacokinetic parameter
|
Point Estimate*
|
90%CI
|
|
Form A
vs
SGC
|
Cmax
|
1.030
|
0.922–1.150
|
|
AUCt
|
1.019
|
0.953–1.090
|
|
AUCinf
|
1.013
|
0.950–1.079
|
|
Form B
vs
SGC
|
Cmax
|
1.094
|
0.967–1.237
|
|
AUCt
|
1.061
|
0.976–1.153
|
|
AUCinf
|
1.050
|
0.969–1.139
|
|
Form C
vs
SGC
|
Cmax
|
1.197
|
1.070–1.339
|
|
AUCt
|
1.144
|
1.067–1.226
|
|
AUCinf
|
1.129
|
1.056–1.206
|
* Antilogarithms of the difference (test vs. reference) of
the least square means for the logarithms.
Conclusions: RTV
prototype tablet formulations A and B met bioequivalence criteria with respect
to RTV Cmax, AUCt, and AUCinf and
warrant further development. Long-term stability evaluations under a variety of
temperature and humidity conditions and additional bioavailability studies are
ongoing to guide selection of a formulation suitable for registration.
|
