Abstract
Purpose
The Hsp90-directed anticancer agent 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) is currently undergoing phase I and phase II clinical investigation. Our goal was to develop a simple limited sampling model (LSM) for AUC of 17-AAG and its active metabolite, 17-(amino)-17-demethoxygeldanomycin (17-AG) using drug concentrations from a few time points.
Methods
Pharmacokinetic data from 34 patients treated at 11 dose levels on a Mayo Clinic Cancer Center phase I clinical trial of 17-AAG was utilized. Blood samples were collected at 11 different time points, spanning 25 h. Graphical methods and correlations were used to assess functional forms and univariate relationships. Multivariate linear regression and bootstrap resampling were used to develop the LSM.
Results
Using log-transformed data, the two and three time point 17-AAG LSMs are log-AUC (17-AAG) = 0.869 + 0.653*(C55min) +0.469*(C5h) and log-AUC (17-AAG) = 2.449 + 0.400*(C55min) +0.441*(C5h) +0.142*(C9h). The two and three time point LSMs for 17-AG are log-AUC (17-AG) = 3.590 + 0.747*(C5h) +0.169*(C17h), and log-AUC (17-AG) = 3.797 + 0.650*(C5h) +0.111*(C9h) +0.122*(C17h). Ninety-seven percent and 94% of the predicted log-AUC values were within 5% of the observed log-AUC for the two and three time point models for 17-AAG and 17-AG respectively.
Conclusions
The precise calculation of AUC is cumbersome and expensive in terms of patient and clinical resources. The LSM developed using a multivariate regression approach is clinically and statistically meaningful. Prospective validation is underway.
Similar content being viewed by others
References
Banerji U, O’Donnel A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons L, Maloney A, Raynaud F, Campbell M, Walton M, Lakhani S, Kaye S, Workman P, Judson I. (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23(18):4152–4161
Banerji U, Walton M, Raynaud F, Grimshaw R, Kelland L, Valenti M, Judson I, Workman P (2005) Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin Cancer Res 11:7023–7032
Beal SL (2001) Ways to fit a PK model with some data below the quantification limit. (erratum appears in J Pharmacokin Pharmacodyn 2002 Jun;29(3):309). J Pharmacokinet Pharmacodyn October 28(5):481–504
Chen X, Bies RR, Ramanathan RK, Zuhowski EG, Trump DL, Egorin MJ (2005) Population Pharmacokinetic analysis of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) in adults with advanced malignancies. Cancer Chemother Pharmacol 55(3):237–243
Conover WJ (1980) Practical nonparametric statistics. Wiley, New York
Efron B (1982) The jackknife, the bootstrap and other resampling plans, regional conference series in applied mathematics, 38. SIAM, Philadelphia
Goetz MP, Toft DO, Ames MM, Erlichman C (2003) The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol 14:1169–1176
Goetz MP, Toft D, Reid J, Ames M, Stensgard B, Safgren S, Adjei AA, Sloan J, Atherton P, Vasile V, Salazaar S, Adjei A, Croghan G, Erlichman C (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23:1078–1087
Jodrell DI, Murray LS, Hawtof J, Graham MA, Egorin MJ (1996) A comparison of methods for limited-sampling strategy design using data from a phase I trial of the anthrapyrazole dup-941. Cancer Chemother Pharmacol 37:356–362
Lindsey JK, Jones B, Jarvis P (2001) Some statistical issues in modelling pharmacokinetic data. Stat Med 20:2775–2783
Neckers L (2002) Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8:S55–S61
Nowakowski G, McCollum A, Ames M, Mandrekar SJ, Reid J, Adjei AA, Toft D, Erlichman C (2006) Phase I trial of twice a week schedule of 17-allylamino-geldanamycin in patients with advanced cancer: pharmacokinetic and pharmacodynamic correlates. Clin Cancer Res 12:6087–6093
Ramanathan RK, Trump DL, Eiseman JL, Belani CP, Agarwala SS, Zuhowski EG, Lan J, Potter DM, Ivy SP, Ramalingam S, Brufsky AM, Wong MK, Tutchko S, Egorin MJ (2005) Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 11(9):3385–3391
Schoemaker RC, Cohen AF (1996) Estimating impossible curves with NONMEM. Br J Clin Pharmacol 42(3):283–290
Shen M, Schilder RJ, Obasaju C, Gallo JM (2002) Population pharmacokinetic and limited sampling models for carboplatin administered in high-dose combination regimens with peripheral blood stem cell support. Cancer Chemother Pharmacol 50:243–250
Sloan JA, Atherton P, Reid J, Pitot HC, Erlichman C, Schaaf L (2001) Limited sampling models for CPT−11, SN−38, and SN−38 glucuronide. Cancer Chemother Pharmacol 48:241–249
Workman P (2003) Overview: translating Hsp90 biology into Hsp90 drugs. Curr Cancer Drug Targets 3:297–300
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Furth, A.F., Mandrekar, S.J., Tan, A.D. et al. A limited sample model to predict area under the drug concentration curve for 17-(allylamino)-17-demethoxygeldanamycin and its active metabolite 17-(amino)-17-demethoxygeldanomycin. Cancer Chemother Pharmacol 61, 39–45 (2008). https://doi.org/10.1007/s00280-007-0443-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-007-0443-6