Dual Incorporation of the in vitro Data (IC₅₀) and in vivo (C_max) Data for the Prediction of Area Under the Curve (AUC) for Statins using Regression Models Developed for Either Pravastatin or Simvastatin

Abstract

Linear regression models utilizing a single time point (C_max) has been reported for pravastatin and simvastatin. A new model was developed for the prediction of AUC of statins that utilized the slopes of the above 2 models, with pharmacokinetic (C_max) and a pharmacodynamic (IC₅₀ value) components for the statins. The prediction of AUCs for various statins (pravastatin, atorvastatin, simvastatin and rosuvastatin) was carried out using the newly developed dual pharmacokinetic and pharmacodynamic model. Generally, the AUC predictions were contained within 0.5 to 2-fold difference of the observed AUC suggesting utility of the new models. The root mean square error predictions were<45% for the 2 models. On the basis of the present work, it is feasible to utilize both pharmacokinetic (C_max) and pharmacodynamic (IC₅₀) data for effectively predicting the AUC for statins. Such a new concept as described in the work may have utility in both drug discovery and development stages.

Key words

pravastatin - simvastatin - pharmacokinetics - pharmacodynamics - atorvastatin - rosuvastatin - AUC - C_max - IC₅₀

• References

• 1 Dietschy JM, Wilson JD. Regulation of Cholesterol Metabolism. N Engl J Med 1970; 282: 1128-1138
• 2 Srinivas NR. Limited Sampling Strategy for the Prediction of area under the curve (AUC) of statins: Reliability of a single time point for AUC prediction for pravastatin and simvastatin. Drug Res (Stuttg) 2015; [Epub ahead of print]
• 3 Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev 2002; 20: 303-328
• 4 McTaggart F, Buckett L, Davidson R et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87 (Suppl) 28B-32B
• 5 Azie NE, Brater DC, Becker PA et al. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998; 64: 369-377
• 6 Wu LX, Guo CX, Chen WQ et al. Inhibition of the organic anion-transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment. Br J Clin Pharmacol 2012; 73: 750-757
• 7 Kyrklund C, Backman JT, Neuvonen M et al. Effect of rifampicin on pravastatin pharmacokinetics in healthy subjects. Br J Clin Pharmacol 2004; 57: 181-187
• 8 Triscari J, Swanson BN, Willard DA et al. Steady state serum concentrations of pravastatin and digoxin when given in combination. Br J Clin Pharmacol 1993; 36: 263-265
• 9 Pan HY, Triscari J, DeVault AR et al. Pharmacokinetic interaction between propranolol and the HMG-CoA reductase inhibitorspravastatin and lovastatin. Br J Clin Pharmacol 1991; 31: 665-670
• 10 Gustavson LE, Schweitzer SM, Koehne-Voss S et al. The effects of multiple doses of fenofibrate on the pharmacokinetics of pravastatin and its 3alpha-hydroxy isomeric metabolite. J Clin Pharmacol 2005; 45: 947-953
• 11 Pan WJ, Gustavson LE, Achari R et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol 2000; 40: 316-323
• 12 Krishna R, Garg A, Jin B et al. Assessment of a pharmacokinetic and pharmacodynamic interaction betweensimvastatin and anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Br J Clin Pharmacol 2009; 67: 520-526
• 13 Bernsdorf A, Giessmann T, Modess C et al. Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms. Br J Clin Pharmacol 2006; 61: 440-450
• 14 O'Brien SG, Meinhardt P, Bond E et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 2003; 89: 1855-1859
• 15 Patel CG, Li L, Girgis S et al. Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole. Clin Pharmacol 2011; 3: 13-25
• 16 Kosoglou T, Meyer I, Veltri EP et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol 2002; 54: 309-319
• 17 Hsyu PH, Schultz-Smith MD, Lillibridge JH et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45: 3445-3450
• 18 Whitfield LR, Porcari AR, Alvey C et al. Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J Clin Pharmacol 2011; 51: 378-388
• 19 Hulskotte EG, Feng HP, Xuan F et al. Pharmacokinetic evaluation of the interaction between hepatitis C virus protease inhibitor boceprevir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and pravastatin. Antimicrob Agents Chemother 2013; 57: 2582-2588 20
• 20 Gajula R, Pilli NR, Ravi VB et al. Simultaneous Determination of Atorvastatin and Aspirin in Human Plasma by LC-MS/MS: Its Pharmacokinetic Application. Sci Pharm 2012; 80: 923-940
• 21 Lee JE, van Heeswijk R, Alves K et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine andatorvastatin. Antimicrob Agents Chemother 2011; 55: 4569-4574
• 22 Pham PA, la Porte CJ, Lee LS et al. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother 2009; 53: 4385-4392
• 23 Jung JA, Lee SY, Kim JR et al. A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects. Drug Des Devel Ther 2015; 9: 745-752
• 24 Allred AJ, Bowen CJ, Park JW et al. Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol 2011; 72: 321-329
• 25 Zhang R, Li Y, Jiang X et al. Pharmacokinetics and tolerability of multiple-dose rosuvastatin: An open-label, randomized-sequence, three-way crossover trial in healthy Chinese volunteers. Curr Ther Res Clin Exp 2009; 70: 392-404
• 26 Keskitalo JE, Kurkinen KJ, Neuvonen M et al. No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, androsuvastatin. Br J Clin Pharmacol 2009; 68: 207-213
• 27 He YJ, Zhang W, Tu JH et al. Hepatic nuclear factor 1alpha inhibitor ursodeoxycholic acid influences pharmacokinetics of the organic anion transporting polypeptide 1B1 substrate rosuvastatin and bilirubin. Drug Metab Dispos 2008; 36: 1453-1456
• 28 van de Steeg E, Kleemann R, Jansen HT et al. Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trials. J Pharmacol Exp Ther 2013; 347: 635-644