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Clinical Pharmacokinetic Studies of Enzalutamide.

Gibbons JA, Ouatas T, Krauwinkel W, Ohtsu Y, van der Walt JS, Beddo V, de Vries M, Mordenti J - Clin Pharmacokinet (2015)

Bottom Line: In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism.Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide.In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration-time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child-Pugh Class A and B) versus men with normal hepatic function (n = 14).

View Article: PubMed Central - PubMed

Affiliation: Medivation, Inc., 36th Floor, 525 Market Street, San Francisco, CA, 94105, USA. jackie.gibbons@medivation.com.

ABSTRACT

Background and objectives: Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide.

Methods: Results are reported from five clinical studies.

Results: In a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30-360 mg/day, and intersubject variability was ≤30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration-time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child-Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady-state predose (trough) concentrations (C trough) versus overall survival (n = 1103) showed that active treatment C trough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of C trough was associated with a statistically significant better response.

Conclusions: Enzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day.

No MeSH data available.


Related in: MedlinePlus

Kaplan–Meier exposure–response analysis for exposure to enzalutamide plus N-desmethyl enzalutamide versus overall survival in the intent-to-treat population in the phase III clinical trial (AFFIRM) [2]. Exposure was based on time‐averaged steady-state predose (Ctrough) plasma concentrations that were classified into quartiles. The analysis involved 1103 patients (n = 176 patients in each of Q1, Q2, Q3, and Q4, and n = 399 placebo patients). Ctrough trough plasma concentration, Q exposure quartile
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Fig7: Kaplan–Meier exposure–response analysis for exposure to enzalutamide plus N-desmethyl enzalutamide versus overall survival in the intent-to-treat population in the phase III clinical trial (AFFIRM) [2]. Exposure was based on time‐averaged steady-state predose (Ctrough) plasma concentrations that were classified into quartiles. The analysis involved 1103 patients (n = 176 patients in each of Q1, Q2, Q3, and Q4, and n = 399 placebo patients). Ctrough trough plasma concentration, Q exposure quartile

Mentions: The exposure-response analysis examined the relationships between Ctrough quartiles for the sum of enzalutamide plus N-desmethyl enzalutamide and the efficacy endpoint of overall survival (ESM 3). The Kaplan–Meier exposure–response curves of overall survival for the composite sum of enzalutamide plus N-desmethyl enzalutamide are shown in Fig. 7. In all pairwise comparisons versus placebo, the effects of the active treatment Ctrough quartile groups were statistically significant (p ≤ 0.0001) in favor of active treatment, supporting the conclusion that the enzalutamide treatment was statistically superior to placebo for overall survival (Fig. 8). In addition, all assessments of overall survival versus the sum of enzalutamide plus N-desmethyl enzalutamide Ctrough values as a continuous variable resulted in statistically significant slopes (p < 0.0001). Although this suggests an association between higher levels of exposure and improved prognosis for patients, pairwise tests showed no difference in the risk of events among active treatment Ctrough quartiles (p ≥ 0.5499) (Fig. 7). Thus, the active treatment Ctrough quartile groups were uniformly beneficial relative to placebo, and there was no specific threshold of plasma concentrations in patients receiving enzalutamide that was associated with achieving a statistically significant better response. Similar results were obtained for exposure–response analyses based on Ctrough values for enzalutamide alone and N-desmethyl enzalutamide alone. Overall, the exposure‐response analysis showed similar efficacy in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day.Fig. 7


Clinical Pharmacokinetic Studies of Enzalutamide.

Gibbons JA, Ouatas T, Krauwinkel W, Ohtsu Y, van der Walt JS, Beddo V, de Vries M, Mordenti J - Clin Pharmacokinet (2015)

Kaplan–Meier exposure–response analysis for exposure to enzalutamide plus N-desmethyl enzalutamide versus overall survival in the intent-to-treat population in the phase III clinical trial (AFFIRM) [2]. Exposure was based on time‐averaged steady-state predose (Ctrough) plasma concentrations that were classified into quartiles. The analysis involved 1103 patients (n = 176 patients in each of Q1, Q2, Q3, and Q4, and n = 399 placebo patients). Ctrough trough plasma concentration, Q exposure quartile
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4580721&req=5

Fig7: Kaplan–Meier exposure–response analysis for exposure to enzalutamide plus N-desmethyl enzalutamide versus overall survival in the intent-to-treat population in the phase III clinical trial (AFFIRM) [2]. Exposure was based on time‐averaged steady-state predose (Ctrough) plasma concentrations that were classified into quartiles. The analysis involved 1103 patients (n = 176 patients in each of Q1, Q2, Q3, and Q4, and n = 399 placebo patients). Ctrough trough plasma concentration, Q exposure quartile
Mentions: The exposure-response analysis examined the relationships between Ctrough quartiles for the sum of enzalutamide plus N-desmethyl enzalutamide and the efficacy endpoint of overall survival (ESM 3). The Kaplan–Meier exposure–response curves of overall survival for the composite sum of enzalutamide plus N-desmethyl enzalutamide are shown in Fig. 7. In all pairwise comparisons versus placebo, the effects of the active treatment Ctrough quartile groups were statistically significant (p ≤ 0.0001) in favor of active treatment, supporting the conclusion that the enzalutamide treatment was statistically superior to placebo for overall survival (Fig. 8). In addition, all assessments of overall survival versus the sum of enzalutamide plus N-desmethyl enzalutamide Ctrough values as a continuous variable resulted in statistically significant slopes (p < 0.0001). Although this suggests an association between higher levels of exposure and improved prognosis for patients, pairwise tests showed no difference in the risk of events among active treatment Ctrough quartiles (p ≥ 0.5499) (Fig. 7). Thus, the active treatment Ctrough quartile groups were uniformly beneficial relative to placebo, and there was no specific threshold of plasma concentrations in patients receiving enzalutamide that was associated with achieving a statistically significant better response. Similar results were obtained for exposure–response analyses based on Ctrough values for enzalutamide alone and N-desmethyl enzalutamide alone. Overall, the exposure‐response analysis showed similar efficacy in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day.Fig. 7

Bottom Line: In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism.Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide.In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration-time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child-Pugh Class A and B) versus men with normal hepatic function (n = 14).

View Article: PubMed Central - PubMed

Affiliation: Medivation, Inc., 36th Floor, 525 Market Street, San Francisco, CA, 94105, USA. jackie.gibbons@medivation.com.

ABSTRACT

Background and objectives: Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide.

Methods: Results are reported from five clinical studies.

Results: In a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30-360 mg/day, and intersubject variability was ≤30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration-time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child-Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady-state predose (trough) concentrations (C trough) versus overall survival (n = 1103) showed that active treatment C trough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of C trough was associated with a statistically significant better response.

Conclusions: Enzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day.

No MeSH data available.


Related in: MedlinePlus