Abstract
Objective
The purpose of this study was to characterize pharmacokinetics of tadalafil (Cialis) and potential sources of variability in patients with erectile dysfunction (ED).
Methods
Population models were developed to describe tadalafil pharmacokinetics in 227 patients with mild to severe ED in a phase III trial. Parallel groups of patients received 2, 5, or 10 mg tadalafil or placebo orally, as needed, for 12 weeks.
Results
Tadalafil pharmacokinetics in patients with ED were linear with respect to dose and duration of treatment, and a one-compartment model adequately described the data. The absorption rate was rapid (1.86 h−1), and the typical population estimates of the apparent oral clearance (CL/F) and apparent volume of distribution were 1.6 l/h and 63.8 l, respectively. Disposition parameters showed a moderate degree of interindividual variability (39–45%). The value of CL/F decreased slightly with increasing serum γ-glutamyl transferase (GGT) concentration, the only statistically significant covariate detected. Systemic exposure to tadalafil was not influenced by age, weight, smoking status, alcohol consumption, liver enzyme status, ED severity, cardiovascular condition, or diabetes mellitus.
Conclusion
Pharmacokinetics in the efficacy/safety trial population are essentially similar to pharmacokinetics in healthy subjects, and no patient-specific factor warranting clinical consideration of dose regimen adjustment was identified in these analyses.
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References
Ayta IA, McKinlay JB, Krane RJ (1999) The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. Br J Urol Int 84(1):50–56
Corbin JD, Francis SH (1999) Cyclic GMP phosphodiesterase 5: target of sildenafil. J Biol Chem 274(20):13729–13732
Francis SH, Corbin JD (2003) Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists. Curr Urol Rep 4(6):457–465
Montorsi F, Verheyden B, Meuleman E, Junemann KP, Moncada I, Valiquette L, Casabe A, Pacheco C, Denne J, Knight J, Segal S, Watkins VS (2004) Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol 45(3):339–344
Carson CC, Rajfer J, Eardley I, Carrier S, Denne JS, Walker DJ, Shen W, Cordell WH (2004) The efficacy and safety of tadalafil: an update. Br J Urol Int 93(9):1276–1281
Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE, Mitchell MI (2006) Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 61(3):280–288
Ring BJ, Patterson BE, Mitchell MI, Vandenbranden M, Gillespie J, Bedding AW, Jewell H, Payne CD, Forgue ST, Eckstein J, Wrighton SA, Phillips DL (2005) Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo. Clin Pharmacol Ther 77(1):63–75
Forgue ST, Phillips DL, Bedding AW, Payne CD, Jewell H, Patterson BE, Wrishko RE, Mitchell MI (2006) Effects of gender, age, diabetes mellitus, and renal and hepatic impairment on tadalafil pharmacokinetics. Br J Clin Pharmacol 63(1):24–35
Staab A, Tillmann C, Forgue ST, Mackie A, Allerheiligen SRB, Rapado J, Trocóniz IF (2004) Population dose-response model for tadalafil in the treatment of male erectile dysfunction. Pharm Res 21(8):1463–1470
Trocóniz IF, Tillmann C, Staab A, Rapado J, Mackie A, Mitchell M, Patterson B, Forgue ST (2003) Tadalafil population pharmacokinetics in patients with erectile dysfunction. AAPS PharmSci 5(4):T2341
Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH (1999) Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 54(2):346–351
US Department of Health and Human Services Food and Drug Administration (1999) Guidance for industry. Population Pharmacokinetics. US Department of Health and Human Services Food and Drug Administration, Washington DC
Beal SL, Sheiner LB (1992) NONMEM users guides. NONMEM Project Group, University of California at San Francisco, San Francisco CA
Karlsson MO, Sheiner LB (1993) The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 21(6):735–750
Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 9(4):503–512
Acknowledgements
We are grateful for the many contributions of our former Lilly Research Centre colleagues, particularly Drs. Alison Mackie and Beverley Patterson. We thank Elizabeth Peck for analytical support and Dr. Diane Phillips for managing all analytical aspects, Karen Schneck for the power analysis of age, and Drs. Vikram Sinha and Malcolm Mitchell for their review of the manuscript.
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This research was funded by Lilly ICOS LLC, Indianapolis, IN, and Bothell, WA.
Financial disclosure
Authors are present (S.T. Forgue) or previous (A. Staab, C. Tillmann) employees of Eli Lilly and Company or have received financial contractual support from this company (I. Troconiz, J. Rapado). S.T. Forgue owns stock in Eli Lilly & Company.
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Trocóniz, I.F., Tillmann, C., Staab, A. et al. Tadalafil population pharmacokinetics in patients with erectile dysfunction. Eur J Clin Pharmacol 63, 583–590 (2007). https://doi.org/10.1007/s00228-007-0297-1
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DOI: https://doi.org/10.1007/s00228-007-0297-1