Abstract
Purpose: The objectives of these population pharmacokinetic analyses were to (1) assess the overall disposition of pemetrexed, (2) characterize between-patient and within-patient variability and identify influential covariates with respect to pemetrexed pharmacokinetics; and, (3) provide individual empirical Bayesian estimates of pharmacokinetic parameters for use in a subsequent pharmacokinetic/pharmacodynamic evaluation of neutropenia following pemetrexed administration. Patients and methods: Data from 287 patients who received 441 cycles without folic acid or vitamin B12 supplementation during participation in one of ten phase II cancer trials were evaluated by population pharmacokinetic analysis using NONMEM. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area, administered as 10-min intravenous infusions every 21 days (1 cycle). The model was developed using data from eight of the ten studies. Predictive performance was evaluated using data from the other two studies. Results: The population pharmacokinetics of pemetrexed administered as a 10-min intravenous infusion are well characterized by a two-compartment model. Typical values of total systemic clearance, central volume of distribution, distributional clearance, and peripheral volume of distribution were 91.6 ml/min, 12.9 l, 14.4 ml/min, and 3.38 l, respectively. Based on these parameter estimates, the terminal elimination half-life of pemetrexed was approximately 3.5 h. Renal function was identified as a covariate with respect to total systemic clearance, and body surface area as a covariate with respect to the central volume of distribution. Conclusion: Total systemic exposure (AUC) for a given dose of pemetrexed increases as renal function decreases. Since pharmacodynamic analyses have shown that AUC and not C max is the primary determinant of neutropenic response to pemetrexed, this suggests that dose adjustments based on renal function, rather than body surface area, might be considered for pemetrexed.
Similar content being viewed by others
References
Adjei AA (2003) Pemetrexed (Alimta): a novel multitargeted antifolate agent. Expert Rev Anticancer Ther 3:145–156
Allen RH, Stabler SP, Savage DG, Lindenbaum J (1993) Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J 7:1344–1353
Bajetta E, Celio L, Buzzoni R et al (2003) Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer. Ann Oncol 14:1543–1548
Beal SL, Sheiner LB (1992) NONMEM users guide. NONMEM project group, University of California, San Francisco
Bunn P, Paoletti P, Niyikiza C et al (2001) Vitamin B12 and folate reduce toxicity of ALIMTA (pemetrexed disodium, LY231514, MTA), a novel antifolate/antimetabolite. Proc Am Soc Clin Oncol 20:76a
Calvert AH, Newell DR, Gumbrell LA et al (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748–1756
Chaudhary AK, Schannen V, Knadler MP, Lantz R, Le Lacheur RM (1999) Analysis of LY231514 by LC/MS/MS. Proceedings 47th ASMS conference on Mass Spectrometry Allied Topics, Dallas, TX
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41
Cripps C, Burnell M, Jolivet J et al (1999) Phase II study of first-line LY231514 (multitargeted antifolate) in patients with locally advanced or metastatic colorectal cancer: an NCIC Clinical Trials Group study. Ann Oncol 10:1175–1179
Egorin MJ (2003) Horseshoes, hand grenades, and body-surface area-based dosing: aiming for a target. J Clin Oncol 21:182–183
Eli Lilly and Company (2004) Package insert: Alimta, pemetrexed for injection
Ette EI (1997) Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 37:486–495
Felici A, Verweij J, Sparreboom A (2002) Dosing strategies for anticancer drugs: the good, the bad, and body-surface area. Eur J Cancer 38:1677–1684
Goedhals L,van Wijk AL (1998) MTA (LY231514) in advanced carcinoma of the cervix. Ann Oncol 9(suppl 4):70
Grem JL (1990) Fluorinated pyrimidines. In: Chabner BA, Collins JM (eds) Cancer chemotherapy: principles and practice. Lippincott, Philadelphia, pp 180–224
Grindey GB, Shih C, Barnett CJ et al (1992) LY231514, a novel pyrrolopyrimidine antifolate that inhibits thymidylate synthase (TS). Proc Am Assoc Cancer Res 33:411
Hanna N, Shepherd FA, Fossella FV et al (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–1597
Latz JE, Karlsson MO, Rusthoven JJ, Ghosh A, Johnson RD (2006) A semimechanistic-physiologic population pharmacokinetic/pharmacodynamic model for neutropenia following pemetrexed therapy. Cancer Chemother Pharmacol. DOI 10.1007/s00280-005-0077-5
Latz JE, Rusthoven JJ, Karlsson MO, Ghosh A, Johnson RD (2006) Clinical application of a semimechanistic-physiologic population PK/PD model for neutropenia following pemetrexed therapy. Cancer Chemother Pharmacol. DOI 10.1007/s00280-005-0035-2
Mandema JW, Verotta D, Sheiner LB (1992) Building population pharmacokinetic-pharmacodynamic models. I. Models for covariate effects. J Pharmacokinet Biopharm 20:511–528
McDonald AC, Vasey PA, Adams L et al (1998) A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res 4:605–610
Mentre F, Ebelin ME (1997) Validation of population pharmacokinetic/pharmacodynamic analyses: review of proposed approaches. In: Balant LP, Aarons L (eds) The Population Approach: Measuring and Managing Variability in Response, Concentration and Dose. Commission of the European Communities, Brussels, pp 147–160
Miller KD, Picus J, Blanke C et al (2000) Phase II study of the multitargeted antifolate LY231514 (ALIMTA, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer. Ann Oncol 11:101–103
Mita AC, Sweeney CJ, Baker SD et al (2005) A phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function [manuscript in press]
Niyikiza C, Baker SD, Seitz DE et al (2002) Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 1:545–552
Niyikiza C, Hanauske AR, Rusthoven JJ et al (2002) Pemetrexed safety and dosing strategy. Semin Oncol 29(6 Suppl 18):24–29
O’Dwyer PJ, Nelson K, Thornton DE (1999) Overview of phase II trials of MTA in solid tumors. Semin Oncol 26:99–104
Ouellet D, Periclou AP, Johnson RD, Woodworth JR, Lalonde RL (2000) Population pharmacokinetics of pemetrexed disodium (ALIMTA) in patients with cancer. Cancer Chemother Pharmacol 46:227–234
Paz-Ares L, Tabernero J, Moyano A et al (1999) Significant activity of the multitargeted antifolate MTA (LY231514) in advanced transitional cell carcinoma (TCC) of the bladder: results of a phase II trial. Eur J Cancer 35(suppl 2):S81
Pivot X, Raymond E, Laguerre B et al (2001) Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 85:649–655
Ratain MJ (1998) Body-surface area as a basis for dosing of anticancer agents: science, myth, or habit? J Clin Oncol 16:2297–2298
Reilly JJ, Workman P (1993) Normalisation of anticancer drug dosage using body weight and surface area: is it worthwhile? A review of theoretical and practical considerations. Cancer Chemother Pharmacol 32:411–418
Rinaldi DA (1999) Overview of phase I trials of multitargeted antifolate (MTA, LY231514). Semin Oncol 26(2 Suppl 6):82–88
Rinaldi DA, Burris HA, Dorr FA et al (1995) Initial phase I evaluation of the novel thymidylate synthase inhibitor LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol 13:2842–2850
Rinaldi DA, Kuhn JG, Burris HA et al (1999) A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 44:372–380
Rusthoven JJ, Eisenhauer E, Butts C et al (1999) Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small cell lung cancer: a phase II study. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 17:1194–1199
Sawyer M, Ratain MJ (2001) Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19:171–177
Scagliotti GV, Shin DM, Kindler HL et al (2003) Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 21:1556–1561
Schilsky RL (1992) Antimetabolites. In: Perry MC (ed) The Chemotherapy Source Book. Williams & Wilkins, Baltimore, pp 301–317
Shargel L, Yu ABC (1985) Applied biopharmaceutics, 2nd ed. Appleton-Century-Crofts, Norwalk, pp 310–312
Sheiner LB (1986) Analysis of pharmacokinetic data using parametric models. III. Hypothesis tests and confidence intervals. J Pharmacokinet Biopharm 14:539–555
Sheiner LB, Steimer JL (2000) Pharmacokinetic/pharmacodynamic modeling in drug development. Annu Rev Pharmacol Toxicol 40:67–95
Shih C, Gosset L, Gates S et al (1996) LY231514 and its polyglutamates exhibit potent inhibition against both human dihydrofolate reductase (DHFR) and thymidylate synthase (TS): multiple folate enzyme inhibition. Ann Oncol 7(Suppl 1):85
Spielmann M, Martin M, Namer M, duBois A, Unger C, Dodwell DJ (2001) Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis. Clin Breast Cancer 2:47–51
Sun H, Fadiran EO, Jones CD et al (1999) Population pharmacokinetics. A regulatory perspective. Clin Pharmacokinet 37:41–58
Vogelzang NJ, Rusthoven JJ, Symanowski J et al (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644
Acknowledgements
The authors wish to thank Dinesh Dealwis (scientific advisor), Mary Brandes Dugan and Pete Fairfield (scientific writing and editorial support), and David B Radtke (operations and project management) for their assistance with the conduct of these analyses and preparation of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Additional information
Robert D Johnson was an employee of Eli Lilly and Company, Indianapolis, USA, at the time this work was completed
Rights and permissions
About this article
Cite this article
Latz, J.E., Chaudhary, A., Ghosh, A. et al. Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients. Cancer Chemother Pharmacol 57, 401–411 (2006). https://doi.org/10.1007/s00280-005-0036-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-005-0036-1