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The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole.
Br J Clin Pharmacol. 2009 Sep; 68(3):381-5.BJ

Abstract

AIMS

Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated.

METHODS

This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration.

RESULTS

Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C(max) by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 +/- 128 to 678 +/- 189 ng ml(-1) and increased AUC by 4.6-fold (4.1, 5.2) from 1666 +/- 808 to 7378 +/- 3011 ng ml(-1) h. Sotrastaurin half-life was nearly doubled from 5.9 +/- 1.7 to 10.6 +/- 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations.

CONCLUSIONS

The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.

Authors+Show Affiliations

Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@novartis.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19740395

Citation

Kovarik, John M., et al. "The Effect On Sotrastaurin Pharmacokinetics of Strong CYP3A Inhibition By Ketoconazole." British Journal of Clinical Pharmacology, vol. 68, no. 3, 2009, pp. 381-5.
Kovarik JM, Huang HL, Slade A, et al. The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole. Br J Clin Pharmacol. 2009;68(3):381-5.
Kovarik, J. M., Huang, H. L., Slade, A., Sfikas, N., & Chandler, P. A. (2009). The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole. British Journal of Clinical Pharmacology, 68(3), 381-5. https://doi.org/10.1111/j.1365-2125.2009.03457.x
Kovarik JM, et al. The Effect On Sotrastaurin Pharmacokinetics of Strong CYP3A Inhibition By Ketoconazole. Br J Clin Pharmacol. 2009;68(3):381-5. PubMed PMID: 19740395.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole. AU - Kovarik,John M, AU - Huang,Hsun-Lun A, AU - Slade,Alan, AU - Sfikas,Nikos, AU - Chandler,Patricia A, PY - 2009/9/11/entrez PY - 2009/9/11/pubmed PY - 2010/4/17/medline SP - 381 EP - 5 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 68 IS - 3 N2 - AIMS: Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated. METHODS: This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration. RESULTS: Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C(max) by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 +/- 128 to 678 +/- 189 ng ml(-1) and increased AUC by 4.6-fold (4.1, 5.2) from 1666 +/- 808 to 7378 +/- 3011 ng ml(-1) h. Sotrastaurin half-life was nearly doubled from 5.9 +/- 1.7 to 10.6 +/- 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations. CONCLUSIONS: The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered. SN - 1365-2125 UR - https://www.unboundmedicine.com/medline/citation/19740395/The_effect_on_sotrastaurin_pharmacokinetics_of_strong_CYP3A_inhibition_by_ketoconazole_ L2 - https://doi.org/10.1111/j.1365-2125.2009.03457.x DB - PRIME DP - Unbound Medicine ER -