CYP2C8 and Drug Interactions FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee meeting, November 18. 2003, Rockville, MD CYP2C8 and Drug Interactions Pertti J. Neuvonen, MD Department of Clinical Pharmacology University of Helsinki & Helsinki University Central Hospital Helsinki, Finland

Outline Expression and Substrates of CYP2C8 Inhibitors of CYP2C8 Inducers of CYP2C8 In vivo interaction studies with CYP2C8 substrates Suggestions for in vitro and in vivo studies

CYP2C8 expression CYP2C8 is highly expressed in the liver (CYP2C protein content: CYP2C9 >~ CYP2C8 > CYP2C19) large interindividual variation not detectable in the intestine (Läpple et al., Pharmacogenetics 2003)

Substrates of CYP2C8 Paclitaxel (taxol); (-> 6-alpha-OH-paclitaxel) Amodiaquine (-> N-desethyl-amodiaquine) Torsemide (-> tolyl-methyl-OH-T; CYP2C9 > CYP2C8) Cerivastatin (CYP2C8 > CYP3A4) Repaglinide (CYP2C8 > CYP3A4) Rosiglitazone (CYP2C8 > CYP2C9) Several other drugs; Contribution of different CYPs may depend on substrate concentration

Amodiaquine metabolism and paclitaxel 6-alphahydroxylase activity 10 human livers (Li et al., JPET 2002)

Inhibitors of CYP2C8: trimethoprim competitive inhibitor of CYP2C8 (Ki 32 µM), relatively selective up to 100 µM

Inhibition of CYPs by trimethoprim CYP2C8 (Ki 32 µM) (Wen et al., DMD 2002)

Inhibition of CYPs by trimethoprim (Wen et al., DMD 2002)

Inhibitors of CYP2C8 Trimethoprim Quercetin competitive inhibitor of CYP2C8 (Ki 2 µM), inhibits also CYP1A2 ”Glitazones” (thiazolidinediones) Gemfibrozil; nonselective; in vitro and in vivo Other nonselective inhibitors

Ki values for glitazones CYP2C8 CYP2C9 CYP3A4 Rosiglitazone 5.59 29.9 36.3 Pioglitazone 1.69 32.1 11.8 Troglitazone 2.59 0.63 1.6 (Sahi et al., DMD 2003) (Ki values, microM)

Diethyldithiocarbamate Inhibition of CYP2C8 by prototypic CYP isoform ”selective” probes Diethyldithiocarbamate also CYP2C8 inhibitor CYP2E1 Ketoconazole also CYP2C8 inhibitor CYP3A (Ong et al., BrJCp 2000)

Induction of CYP2C8 In vitro: CYP2C8 is inducible Rifampin: CYP2C8 >CYP2C19, CYP2C9 Rifampin>Phenobarb.>Dexamethasone (Raucy et al., JPET 2002) In vivo: Rifampin decreases the AUC of repaglinide by about 60% (30-78%) (Niemi et al., CPT 2000)

In vivo studies: Gemfibrozil + Statins / Oral Antidiabetics Randomized, cross-over, healthy volunteers Gemfibrozil 1200 mg/d or placebo/comparator for 3-4 days On day 3, a single dose of Cerivastatin Simvastatin Lovastatin (Gemfibrozil, Bezafibrate, Placebo) Repaglinide (Gemfibr., Itraconazol, Gem+Itra, Plac) Rosiglitazone

Effect of gemfibrozil on cerivastatin PK Cerivastatin (acid) Cerivastatin lactone AUC x 5-6 M-23 metabolite CYP2C8 M-1 metabolite CYP3A4 (Backman et al. CPT 2002)

Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) in vitro Rate of metabolite formation M23; CYP2C8 (Wang et al. DMD 2002)

Gemfibrozil increases the AUC of simvastatin acid but NOT of the parent simvastatin Gemfibrozil: Simvastatin acid: AUC x 2.3 Simvastatin AUC: ~ Placebo (Backman et al. CPT 2000)

CYP-enzymes in simvastatin metabolism Carboxyl-esterase Simvastatin (0) CYP3A4 Simvastatin acid (100) CYP3A4, CYP2C8 corresponding (active) acids (Gruer et al., Am J Cardiol 1999; Prueksaritanont et al. BrJCP 2003)

Gemfibrozil unlike bezafibrate increases the AUC of lovastatin acid but NOT of the parent lovastatin Lovastatin AUC: ~ Gemfibrozil 600 mg x 2 Lovastatin acid AUC: x 2.8 Bezafibrate 400 mg x 1 Placebo (Kyrklund et al,. CPT 2001)

(Niemi et al., Diabetologia 2003) Effect of gemfibrozil, itraconazole and their combination on plasma repaglinide and its M1-metabolite Gem 600mg x 2 Gem+itra Itra 200mg x 1 M1-metabolite; CYP3A4 Repaglinide Gem 600mg x 2 Placebo Gem+itra Placebo Itra n (Niemi et al., Diabetologia 2003)

Effect of CYP3A4 inhibitors and gemfibrozil on the AUC of repaglinide Repaglinide AUC (Niemi et al. CPT 2001, Diabetologia 2003)

Effect of Gemfibrozil on Rosiglitazone Rosiglitazone AUC x 2.3 Gemfibrozil Placebo (Niemi et al., Diabetologia 2003)

CYP2C8: in vitro interaction studies Human liver microsomes, or recombinant human CYP2C8 isoform Substrates: paclitaxel, amodiaquine torsemide (only with recombinant CYP2C8) Inhibitors: trimethoprim, quercetin, pio/rosiglitazone Inducers: rifampin

CYP2C8: in vivo interaction studies Probe substrates: repaglinide (obs. hypoglycemia) rosiglitazone cerivastatin? (availability?); amodiaquine?? (toxic) Inhibitors: gemfibrozil (nonselective, e.g. CYP2C9 and OATP2) trimethoprim (in vivo data as inhibitor?) pio/rosiglitazone (in vivo data as inhibitors?) Inducers: rifampin (nonselective) Further studies are needed to find optimal probe substrates and inhibitors, particularly for in vivo interaction studies