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Pharmacokinetic Drug Interaction Studies with Enzalutamide.

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

Bottom Line: Enzalutamide did not affect exposure to oral pioglitazone.If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day.It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.

View Article: PubMed Central - PubMed

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

ABSTRACT

Background and objectives: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

Methods: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).

Results: Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4.

Conclusions: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.

No MeSH data available.


Related in: MedlinePlus

Schematic of the phase I fixed-sequence crossover drug interaction study with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates in patients with metastatic castration-resistant prostate cancer. CYP cytochrome P450. aEnzalutamide placebo-to-match capsules were filled with caprylocaproyl polyoxylglycerides and administered under fasting conditions on days 1 and 5. bPatients were instructed to take enzalutamide (160 mg) on days 13–97 as close to the same time each day as possible; enzalutamide could be taken with or without food, except on days 55 and 62, when it was administered under fasting conditions. cPioglitazone (30 mg) was administered under fasting conditions on days 1 and 55. dThe oral drug cocktail, which consisted of warfarin (10 mg), omeprazole (20 mg), and midazolam (2 mg), was administered under fasting conditions on days 5 and 62
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Fig1: Schematic of the phase I fixed-sequence crossover drug interaction study with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates in patients with metastatic castration-resistant prostate cancer. CYP cytochrome P450. aEnzalutamide placebo-to-match capsules were filled with caprylocaproyl polyoxylglycerides and administered under fasting conditions on days 1 and 5. bPatients were instructed to take enzalutamide (160 mg) on days 13–97 as close to the same time each day as possible; enzalutamide could be taken with or without food, except on days 55 and 62, when it was administered under fasting conditions. cPioglitazone (30 mg) was administered under fasting conditions on days 1 and 55. dThe oral drug cocktail, which consisted of warfarin (10 mg), omeprazole (20 mg), and midazolam (2 mg), was administered under fasting conditions on days 5 and 62

Mentions: As summarized in Fig. 1, a single oral dose of pioglitazone 30 mg was given on day 1, followed by a 4-day washout. On day 5, a single oral cocktail of warfarin 10 mg (racemic mixture of R- and S-warfarin), omeprazole 20 mg, and midazolam 2 mg was administered, followed by a washout period of 8 days. On days 1 and 5, patients received a single oral dose of enzalutamide placebo-to-match, which was identical to the enzalutamide drug product presentation except that it lacked the drug substance. The purpose of the placebo-to-match was to control for possible effects of excipients (caprylocaproyl polyoxylglycerides) on the absorption of the substrate drugs. Patients received oral doses of enzalutamide 160 mg once daily (i.e., the recommended dose for mCRPC) from days 13 to 97. On day 55, a single oral dose of pioglitazone 30 mg was given. After a 7-day washout (i.e., on day 62), patients received a single oral cocktail of warfarin 10 mg, omeprazole 20 mg, and midazolam 2 mg. Patients experiencing clinical benefit at day 97 were permitted to enroll into an extension study in which they could continue receiving enzalutamide 160 mg once daily.Fig. 1


Pharmacokinetic Drug Interaction Studies with Enzalutamide.

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

Schematic of the phase I fixed-sequence crossover drug interaction study with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates in patients with metastatic castration-resistant prostate cancer. CYP cytochrome P450. aEnzalutamide placebo-to-match capsules were filled with caprylocaproyl polyoxylglycerides and administered under fasting conditions on days 1 and 5. bPatients were instructed to take enzalutamide (160 mg) on days 13–97 as close to the same time each day as possible; enzalutamide could be taken with or without food, except on days 55 and 62, when it was administered under fasting conditions. cPioglitazone (30 mg) was administered under fasting conditions on days 1 and 55. dThe oral drug cocktail, which consisted of warfarin (10 mg), omeprazole (20 mg), and midazolam (2 mg), was administered under fasting conditions on days 5 and 62
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4580724&req=5

Fig1: Schematic of the phase I fixed-sequence crossover drug interaction study with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates in patients with metastatic castration-resistant prostate cancer. CYP cytochrome P450. aEnzalutamide placebo-to-match capsules were filled with caprylocaproyl polyoxylglycerides and administered under fasting conditions on days 1 and 5. bPatients were instructed to take enzalutamide (160 mg) on days 13–97 as close to the same time each day as possible; enzalutamide could be taken with or without food, except on days 55 and 62, when it was administered under fasting conditions. cPioglitazone (30 mg) was administered under fasting conditions on days 1 and 55. dThe oral drug cocktail, which consisted of warfarin (10 mg), omeprazole (20 mg), and midazolam (2 mg), was administered under fasting conditions on days 5 and 62
Mentions: As summarized in Fig. 1, a single oral dose of pioglitazone 30 mg was given on day 1, followed by a 4-day washout. On day 5, a single oral cocktail of warfarin 10 mg (racemic mixture of R- and S-warfarin), omeprazole 20 mg, and midazolam 2 mg was administered, followed by a washout period of 8 days. On days 1 and 5, patients received a single oral dose of enzalutamide placebo-to-match, which was identical to the enzalutamide drug product presentation except that it lacked the drug substance. The purpose of the placebo-to-match was to control for possible effects of excipients (caprylocaproyl polyoxylglycerides) on the absorption of the substrate drugs. Patients received oral doses of enzalutamide 160 mg once daily (i.e., the recommended dose for mCRPC) from days 13 to 97. On day 55, a single oral dose of pioglitazone 30 mg was given. After a 7-day washout (i.e., on day 62), patients received a single oral cocktail of warfarin 10 mg, omeprazole 20 mg, and midazolam 2 mg. Patients experiencing clinical benefit at day 97 were permitted to enroll into an extension study in which they could continue receiving enzalutamide 160 mg once daily.Fig. 1

Bottom Line: Enzalutamide did not affect exposure to oral pioglitazone.If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day.It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.

View Article: PubMed Central - PubMed

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

ABSTRACT

Background and objectives: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

Methods: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).

Results: Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4.

Conclusions: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.

No MeSH data available.


Related in: MedlinePlus