General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information.
BACKGROUND
Induction of cytochrome P450 (CYP) 3A4 potentially reduces the blood concentrations of substrate drugs to less than one-tenth, which results in ineffective pharmacotherapy. Although the prediction of drug-drug interactions (DDIs) that are mediated by induction of CYP3A4 has been performed mainly on the basis of in vitro information, such methods have met with limited success in terms of their accuracy and applicability. Therefore, a realistic method for the prediction of CYP3A4-mediated inductive DDIs is of major clinical importance.


OBJECTIVE
The objective of the present study was to construct a robust and accurate method for the prediction of CYP3A4-mediated inductive DDIs. Such a method was developed on the basis of the principle applied for prediction of inhibitory DDIs in a previous report. A unique character of this principle is that the extent of alterations in the area under the plasma concentration-time curve (AUC) is predicted on the basis of in vivo information from minimal clinical studies without using in vitro data.


METHODS
The analysis is based on 42 DDI studies in humans reported in 37 published articles over the period 1983-2007. Kinetic analysis revealed that the reduction in the AUC of a substrate of CYP3A4 produced by consecutive administration of an inducer of CYP3A4 could be approximated by the equation 1/(1 + CRCYP3A4 * ICCYP3A4), where CRCYP3A4 is the ratio of the apparent contribution of CYP3A4 to the oral clearance of a substrate and ICCYP3A4 is the apparent increase in clearance of a substrate produced by induction of CYP3A4. Using this equation, the ICCYP3A4 was calculated for seven inducers (bosentan, carbamazepine, efavirenz, phenytoin, pioglitazone, rifampicin [rifampin], and St John's wort [hypericum]) on the basis of the reduction in the AUC of a coadministered standard substrate of CYP3A4, such as simvastatin, in ten DDI studies. The CRCYP3A4 was calculated for 22 substrates on the basis of the previously reported method from inhibitory DDI studies using a potent CYP3A4 inhibitor such as itraconazole or ketoconazole.


RESULTS
The proposed method enabled the prediction of AUC reduction by CYP3A4 induction with any combination of these substrates and inducers (total 154 matches). To assess the accuracy of the prediction, the AUC reductions in 32 studies were analysed. We found that the magnitude of the deviation between the mean values of the observed and predicted AUCs of all substrate drugs was <20% of the AUCs of the respective substrate drugs before administration of the inducers. In addition, rifampicin was found to be the most potent inducer among the compounds analysed in the present study, with an ICCYP3A4 value of 7.7, followed by phenytoin and carbamazepine, with values of 4.7 and 3.0, respectively. The ICCYP3A4 values of the other CYP3A4 inducers analysed in the present study were approximately 1 or less, which suggests that the AUCs of coadministered drugs may not be reduced to less than approximately half, even if the drug is metabolized solely by CYP3A4.


CONCLUSIONS
By using the method reported in the present study, the susceptibilities of a substrate drug of CYP3A4 to inductive DDIs can be predicted quantitatively. It was indicated that coadministration of rifampicin, phenytoin and carbamazepine may reduce plasma AUCs to less than half for a broad range of CYP3A4 substrate drugs, with CRCYP3A4 values greater than 0.13, 0.21 and 0.33, respectively.
Ohno
Yoshiyuki
Y
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Hisaka
Akihiro
A
Ueno
Masaki
M
Suzuki
Hiroshi
H
D000284:Administration, Oral; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics
D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
Antimicrob Agents Chemother. 2007 Oct;51(10):3617-26
17646413
J Pharmacol Exp Ther. 1997 Dec;283(3):1552-62
9400033
Am J Med. 2002 Dec 15;113(9):746-50
12517365
Drug Metab Dispos. 2006 Jan;34(1):166-75
16221752
Br J Clin Pharmacol. 2001 May;51(5):443-50
11422002
Clin Pharmacol Ther. 1999 Apr;65(4):428-38
10223781
Eur J Clin Pharmacol. 1996;51(3-4):331-4
9010708
Clin Pharmacokinet. 1998 Nov;35(5):361-90
9839089
Clin Pharmacol Ther. 1996 Jan;59(1):7-13
8549036
J Clin Pharm Ther. 2005 Jun;30(3):285-90
15896247
Drug Metab Dispos. 2006 Oct;34(10):1742-8
16837568
Mol Pharmacol. 1999 Dec;56(6):1329-39
10570062
Drug Metab Rev. 1997 Feb-May;29(1-2):413-580
9187528
J Acquir Immune Defic Syndr. 2005 Jul 1;39(3):307-12
15980690
Pharmacogenetics. 1999 Dec;9(6):725-34
10634135
J Biol Chem. 2001 May 4;276(18):14581-7
11297522
Clin Pharmacokinet. 2007;46(2):133-57
17253885
J Clin Invest. 1999 Jul;104(2):147-53
10411543
Drug Metab Dispos. 2003 Jul;31(7):815-32
12814957
Drug Metab Dispos. 1999 Aug;27(8):887-94
10421615
Clin Pharmacol Ther. 2003 Jan;73(1):41-50
12545142
Clin Pharmacokinet. 2003;42(9):819-50
12882588
Pharmacotherapy. 1995 May-Jun;15(3):353-6
7667170
J Clin Invest. 1998 Sep 1;102(5):1016-23
9727070
Clin Pharmacokinet. 2005;44(3):279-304
15762770
Br J Clin Pharmacol. 1999 Nov;48(5):733-42
10594476
Clin Pharmacol Ther. 2007 Feb;81(2):194-204
17192770
Clin Pharmacol Ther. 2004 Oct;76(4):391
15470340
Eur J Clin Pharmacol. 2004 Feb;59(12):879-82
14691614
Clin Pharmacokinet. 2001;40(12):893-905
11735608
Br J Clin Pharmacol. 2000;49 Suppl 1:65S-70S
10771457
Eur J Pharm Sci. 2000 Nov;12(1):3-12
11121729
Br J Clin Pharmacol. 1989 Oct;28(4):373-87
2590599
Drug Metab Dispos. 1990 Sep-Oct;18(5):595-606
1981707
Drug Metab Dispos. 2005 Jun;33(6):764-70
15764714
Am J Obstet Gynecol. 1998 Feb;178(2):300-4
9500490
J Pharmacol Exp Ther. 2005 Feb;312(2):583-91
15523003
Drug Metab Dispos. 2006 Jul;34(7):1229-36
16595711
Eur J Clin Pharmacol. 2004 Aug;60(6):427-30
15232663
Clin Pharmacol Ther. 1992 Nov;52(5):453-7
1424418
Drug Metab Dispos. 1989 Mar-Apr;17(2):197-207
2565211
Drug Metab Dispos. 2005 Oct;33(10):1477-81
16014768
Drug Metab Dispos. 1996 Oct;24(10):1121-3
8894514
Br J Clin Pharmacol. 1984 Dec;18(6):887-93
6529529
J Pharm Sci. 1998 Nov;87(11):1322-30
9811484
Xenobiotica. 2007 Oct-Nov;37(10-11):1196-224
17968743
Br J Clin Pharmacol. 2003 Feb;55(2):203-11
12580993
Clin Pharmacol Ther. 2000 Dec;68(6):592-7
11180018
Clin Pharmacokinet. 2007;46(8):681-96
17655375
Clin Pharmacol Ther. 2005 Aug;78(2):154-67
16084850
Br J Clin Pharmacol. 2006 Jan;61(1):58-69
16390352
Clin Pharmacol Ther. 2001 Oct;70(4):317-26
11673747
Br J Clin Pharmacol. 2005 Nov;60(5):508-18
16236041
Cancer Chemother Pharmacol. 2004 Oct;54(4):290-4
15138710
Cancer Chemother Pharmacol. 2004 Feb;53(2):102-6
14605865
Drug Metab Dispos. 2001 Apr;29(4 Pt 1):443-52
11259329
Clin Pharmacol Ther. 1997 Jan;61(1):8-14
9024169
Drug Metab Pharmacokinet. 2005 Aug;20(4):236-43
16141603
Pharm Res. 1995 Sep;12(9):1304-10
8570526
Pharm Res. 2006 Jun;23(6):1089-116
16718615
Drug Metab Dispos. 2000 Apr;28(4):467-74
10725316
Eur J Clin Pharmacol. 2005 May;61(3):185-8
15776275
Clin Pharmacokinet. 2000 Feb;38(2):111-80
10709776
Pharmacol Toxicol. 1999 Feb;84(2):94-7
10068153
Eur J Clin Pharmacol. 2000 Apr;56(1):57-60
10853878
Eur J Pharm Sci. 2000 Sep;11(3):185-9
11042223
Br J Clin Pharmacol. 1997 Aug;44(2):190-4
9278209
J Clin Pharmacol. 1998 Feb;38(2):112-21
9549641
J Clin Psychopharmacol. 2002 Feb;22(1):46-54
11799342
J Pharm Pharmacol. 2000 Oct;52(10):1265-9
11092571
Obstet Gynecol. 2001 Aug;98(2):218-23
11506836
J Clin Psychopharmacol. 2001 Feb;21(1):89-93
11199955
Br J Clin Pharmacol. 2005 Feb;59(2):199-206
15676042
Kidney Int. 2000 Jan;57(1):224-31
10620203
Pharmacotherapy. 1998 Jan-Feb;18(1):84-112
9469685
Br Med J (Clin Res Ed). 1983 Mar 19;286(6369):923-5
6403136
JAMA. 2003 Sep 17;290(11):1500-4
13129991
Clin Pharmacol Ther. 1997 Dec;62(6):629-34
9433391
Chem Biol Interact. 1997 Nov 6;107(1-2):17-30
9402947
Clin Pharmacol Ther. 2004 Oct;76(4):330-40
15470332
Clin Pharmacokinet. 2005;44(10):1067-81
16176119
Clin Pharmacokinet. 2003;42(3):293-301
12603176
Blood. 2004 Aug 15;104(4):1229-30
15294859
Clin Pharmacol Ther. 2000 Oct;68(4):345-55
11061574
Br J Clin Pharmacol. 1997 May;43(5):471-4
9159561
Clin Pharmacol Ther. 2006 Aug;80(2):126-35
16890574
Clin Pharmacokinet. 2005;44(9):915-34
16122280
Br J Clin Pharmacol. 2006 Nov;62(5):512-26
17010103
Life Sci. 1990;47(22):1981-8
2273938
Drug Metab Dispos. 2005 Jun;33(6):837-44
15897600
Clin Pharmacol Ther. 2001 Mar;69(3):114-21
11240975
Clin Pharmacol Ther. 2006 Apr;79(4):350-61
16580903
Neuropsychopharmacology. 1998 May;18(5):364-9
9536449
Clin Pharmacol Ther. 2003 Dec;74(6):525-35
14663455