Pooled Post Hoc Analysis of Population Pharmacokinetics of @entity1288 and @entity1443 Following Multiple Oral Doses of Biphasic Immediate-Release/Extended-Release @entity1288 / XXXX Tablets.

@entity1 @entity1443 @entity1288 @entity5708
OBJECTIVE: To examine whether biphasic immediate-release (IR)/extended-release (ER) @entity1288 ( @entity5708 )/ @entity1443 ( @entity1443 ) 7.5/325-mg tablets have clinically relevant variability in population pharmacokinetics (PK). DESIGN: Post hoc analysis of 2 phase 1 randomized, open-label, multiple-dose crossover studies. SETTING: Single contract research organization clinic. SUBJECTS: @entity1 and @entity1 aged 18 to 55  years with a body mass index of 19 to 30  kg/m(2) and body weight >=   59  kg. METHODS: Fasted @entity1 (N  =  96) received 2 tablets of IR/ER @entity5708 / @entity1443 7.5/325  mg (total dose, 15/650  mg) every 12  hours for 4.5  days. Population PK analysis was performed using nonlinear mixed effects modeling and evaluated 6 population variables. RESULTS: The average PK estimates for @entity5708 were 75  L/hour for clearance (CL/F), 756  L for volume of distribution (V/F), and 0.581  per hour for absorption rate constant (Ka ). Body weight was a statistically significant source of variability in V/F for @entity5708 at steady state. Average estimates for @entity1443 were 25  L/hour for CL/F and 119  L for V/F. Sex was identified as a statistically significant source of variability in CL/F with predicted values for @entity1443 of 25  L/hour in @entity1 and 21  L/hour in @entity1 . Body weight affected variability in V/F, with a predicted value of 193  L in @entity1 and 174  L in @entity1 for a 72-kg @entity1 at steady state. CONCLUSIONS: Dose adjustments of <  50% are not clinically relevant for IR/ER @entity5708 / @entity1443 7.5/325-mg tablets considering the approved dose of 1 to 2 tablets every 8 to 12  hours; thus, adjustment may be necessary for large deviations from normal body weight but not for sex.
