Dataset Information

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

ABSTRACT: Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.

SUBMITTER: Wind S

PROVIDER: S-EPMC5315738 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

Wind Sven S Schnell David D Ebner Thomas T Freiwald Matthias M Stopfer Peter P

Clinical pharmacokinetics 20170301 3

Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral admi ...[more]

PMID: 27470518

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Project description:Rucaparib is an oral small-molecule poly(ADP-ribose) polymerase inhibitor indicated for patients with recurrent ovarian cancer in the maintenance and treatment settings and for patients with metastatic castration-resistant prostate cancer associated with a deleterious BRCA1 or BRCA2 mutation. Rucaparib has a manageable safety profile; the most common adverse events reported were fatigue and nausea in both indications. Accumulation in plasma exposure occurred after repeated administration of the approved 600-mg twice-daily dosage. Steady state was achieved after continuous twice-daily dosing for a week. Rucaparib has moderate oral bioavailability and can be dosed with or without food. Although a high-fat meal weakly increased maximum concentration and area under the curve, the effect was not clinically significant. A mass balance analysis indicated almost a complete dose recovery of rucaparib over 12 days, with metabolism, renal, and hepatic excretion as the elimination routes. A population pharmacokinetic analysis of rucaparib revealed no effect of age, sex, race, or body weight. No starting dose adjustments were necessary for patients with mild-to-moderate hepatic or renal impairment; the effect of severe organ impairment on rucaparib exposure has not been evaluated. In patients, rucaparib moderately inhibited cytochrome P450 (CYP) 1A2 and weakly inhibited CYP3As, CYP2C9, and CYP2C19. Rucaparib weakly increased systemic exposures of oral contraceptives and oral rosuvastatin and marginally increased the exposure of oral digoxin (a P-glycoprotein substrate). In vitro studies suggested that rucaparib inhibits transporters MATE1, MATE2-K, OCT1, and OCT2. No clinically meaningful drug interactions with rucaparib as a perpetrator were observed. An exposure-response analysis revealed dose-dependent changes in selected clinical efficacy and safety endpoints. Overall, this article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, drug-drug interactions, effects of intrinsic and extrinsic factors, and exposure-response relationships of rucaparib.

Dataset Information

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

Publications

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

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