International journal of clinical pharmacology and therapeutics · 2019
Population pharmacokinetics of tofacitinib in patients with psoriatic arthritis .
Клиническое исследование III фазыСтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Xie Rujia, Deng Chenhui, Wang Qiang, Kanik Keith S, Nicholas Timothy, Menon Sujatha
Аннотация
OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This analysis characterized the pharmacokinetics (PK) of tofacitinib in adult patients with active PsA and evaluated the impact of covariates (baseline characteristics) on the disposition of tofacitinib.
MATERIALS AND METHODS: Data were pooled from two phase 3 studies of tofacitinib of up to 12 months' duration in patients with active PsA (OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439)). This analysis included 650 tofacitinib-treated patients with 3,252 tofacitinib plasma concentration measurements. Tofacitinib PK was described using a one-compartment disposition model parameterized in terms of apparent oral clearance (CL/F) and apparent volume of distribution (V/F) with first-order absorption rate (Ka) and a lag time. Covariates evaluated were baseline age, baseline body weight, sex, race, ethnicity, baseline creatinine clearance (BCCL), and baseline C-reactive protein.
RESULTS: The estimates (95% confidence interval) of PK model parameters of a reference patient were CL/F: 20.4 (18.6, 21.8) L/h; V/F: 110 (108, 113) L; and Ka: 13.8 (12.1, 16.6)/h. Among the covariates, only BCCL led to clinically relevant changes in exposure; however, this was consistent with the known contribution of renal excretion to the total clearance of tofacitinib (~ 30%).
CONCLUSION: Tofacitinib did not require dose modification or restrictions for age, body weight, sex, race, ethnicity, or baseline disease severity in patients with active PsA based on the magnitude of exposure relative to a reference patient. Dosing adjustments for renal impairment were derived from a separate phase 1 study.
MATERIALS AND METHODS: Data were pooled from two phase 3 studies of tofacitinib of up to 12 months' duration in patients with active PsA (OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439)). This analysis included 650 tofacitinib-treated patients with 3,252 tofacitinib plasma concentration measurements. Tofacitinib PK was described using a one-compartment disposition model parameterized in terms of apparent oral clearance (CL/F) and apparent volume of distribution (V/F) with first-order absorption rate (Ka) and a lag time. Covariates evaluated were baseline age, baseline body weight, sex, race, ethnicity, baseline creatinine clearance (BCCL), and baseline C-reactive protein.
RESULTS: The estimates (95% confidence interval) of PK model parameters of a reference patient were CL/F: 20.4 (18.6, 21.8) L/h; V/F: 110 (108, 113) L; and Ka: 13.8 (12.1, 16.6)/h. Among the covariates, only BCCL led to clinically relevant changes in exposure; however, this was consistent with the known contribution of renal excretion to the total clearance of tofacitinib (~ 30%).
CONCLUSION: Tofacitinib did not require dose modification or restrictions for age, body weight, sex, race, ethnicity, or baseline disease severity in patients with active PsA based on the magnitude of exposure relative to a reference patient. Dosing adjustments for renal impairment were derived from a separate phase 1 study.