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.
OBJECTIVE
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*(C(55min)) +0.469*(C(5h)) and log-AUC (17-AAG) = 2.449 + 0.400*(C(55min)) +0.441*(C(5h)) +0.142*(C(9h)). The two and three time point LSMs for 17-AG are log-AUC (17-AG) = 3.590 + 0.747*(C(5h)) +0.169*(C(17h)), and log-AUC (17-AG) = 3.797 + 0.650*(C(5h)) +0.111*(C(9h)) +0.122*(C(17h)). 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.
Furth
Alfred F
AF
Division of Biostatistics, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Mandrekar
Sumithra J
SJ
Tan
Angelina D
AD
Rau
Andrea
A
Felten
Sara J
SJ
Ames
Matthew M
MM
Adjei
Alex A
AA
Erlichman
Charles
C
Reid
Joel M
JM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016227:Benzoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D012494:Sampling Studies
C524971:17-amino-17-demethoxygeldanomycin; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin