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© 2002 American Society for Clinical Oncology Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population AnalysisByFrom the Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, and Department of Medical Oncology, Erasmus MC–Daniel den Hoed, Rotterdam, the Netherlands. Address reprint requests to Mats O. Karlsson, PhD, Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, BMC, SE-751 24 Uppsala, Sweden; email: mats.karlsson{at}farmbio.uu.se
PURPOSE: To build population pharmacokinetic (PK) models for irinotecan (CPT-11) and its currently identified metabolites. PATIENTS AND METHODS: Seventy cancer patients (24 women and 46 men) received 90-minute intravenous infusions of CPT-11 in the dose range of 175 to 300 mg/m2. The PK models were developed to describe plasma concentration profiles of the lactone and carboxylate forms of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) and the total forms of SN-38 glucuronide (SN-38G), 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC) by using NONMEM. RESULTS: The interconversion between the lactone and carboxylate forms of CPT-11 was relatively rapid, with an equilibration half-life of 14 minutes in the central compartment and hydrolysis occurring at a rate five times faster than lactonization. The same interconversion also occurred in peripheral compartments. CPT-11 lactone had extensive tissue distribution (steady-state volume of distribution [Vss], 445 L) compared with the carboxylate form (Vss, 78 L, excluding peripherally formed CPT-11 carboxylate). Clearance (CL) was higher for the lactone form (74.3 L/h) compared with the carboxylate form (12.3 L/h). During metabolite data modeling, goodness of fit indicated a preference of SN-38 and NPC to be formed out of the lactone form of CPT-11, whereas APC could be modeled best by presuming formation from CPT-11 carboxylate. The interconversion between SN-38 lactone and carboxylate was slower than that of CPT-11, with the lactone form dominating at equilibrium. The CLs for SN-38 lactone and carboxylate were similar, but the lactone form had more extensive tissue distribution. CONCLUSION: Plasma data of CPT-11 and metabolites could be adequately described by this compartmental model, which may be useful in predicting the time courses, including interindividual variability, of all characterized substances after intravenous administrations of CPT-11.
IRINOTECAN (CPT-11), as an inhibitor of DNA topoisomerase I, is widely used in the treatment of several types of tumors, including colorectal cancer.1 CPT-11 is extensively metabolized in the liver to various metabolites. It is cleaved enzymatically by carboxylesterases to form 7-ethyl-10-hydroxycamptothecin (SN-38), which has cytotoxic activity that is 100 to 1,000 times greater than that of the parent drug.2 SN-38 is further conjugated to an inactive glucuronide (SN-38G) by uridine diphosphate glucuronosyltransferases.3,4 Other CPT-11 metabolites identified are the major plasma metabolite 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC), resulting from a ring-opening oxidation of the terminal piperidine ring of CPT-11 mediated by cytochrome P450 3A4 enzymes.5,6 CPT-11 and its metabolites contain an alpha-hydroxy-delta-lactone ring, which is chemically unstable and undergoes pH-dependent reversible hydrolysis to a hydroxyl-carboxylate form. An intact lactone group is essential for interaction with the DNA-enzyme complex.7 Therefore, the pharmacokinetics (PK) of CPT-11 lactone and SN-38 lactone are of particular interest. Individual plasma concentrations of CPT-11 and its four currently identified metabolites can be described by three-compartment models.8 Others report that two- or three-compartment models may be used to fit CPT-11 and SN-38 concentration profiles with noncompartmental or compartment approaches.9-12 Ma et al13 have analyzed individual concentration data of total forms of CPT-11, SN-38, and APC simultaneously by using a four-compartmental model with the assumption of an identical volume of distribution for these substances. The PK of the lactone and carboxylate forms of CPT-11 and SN-38 were investigated previously,9-11,14 but parameters other then the area under the curve (AUC) of SN-38 were not estimated. The clinical PK, metabolism, and pharmacodynamics of CPT-11 have been widely studied to date (see reviews9-11). However, for the metabolites, most publications limit the PK analysis to reporting on the AUC ratio of metabolite to parent drug. In this study, we used nonlinear mixed-effect modeling to analyze data from all patients simultaneously and considered the influence of covariates on the PK parameters. The purposes of this study were to build suitable PK models for CPT-11 and four of its metabolites, including lactone and carboxylate forms, to more clearly understand the PK interrelations between the parent drug and metabolites, and to provide potentially useful information for clinical treatment with CPT-11.
Patients and Study Design Patients with a histologically or cytologically proven malignant solid tumor were treated with CPT-11 intravenously between May 1996 and October 1999 at the Erasmus MC (Rotterdam, the Netherlands). Criteria for eligibility included the following: (1) age younger than 75 years; (2) an Eastern Cooperative Oncology Group performance status of  2; (3) adequate hematologic function (WBC  3.0 x 109/L, absolute neutrophil count 2.0 x 109/L, and platelet count 100 x 109/L), hepatic function (total serum bilirubin 1.25 times the upper limit of normal and AST and ALT levels 3.0 times the upper limit of normal), and renal function (serum creatinine 135 µmol/L or creatinine clearance 60 mL/min); (4) no previous anticancer treatment for at least 4 weeks, or 6 weeks in case of nitrosoureas or mitomycin; and (5) no previous therapy with other topoisomerase I inhibitors. The clinical protocol was approved by the Erasmus MC Ethical Board, and all patients gave written, informed consent before study entry. CPT-11 lactone was administered in a 3-weekly regimen as a 90-minute intravenous infusion in the dose range of 175 to 300 mg/m2, after dilution of the pharmaceutical preparation in 250 mL of isotonic sodium chloride. In all patients, premedication consisted of ondansetron (8 mg intravenously) combined with dexamethasone (10 mg intravenously), both administered 30 minutes before the start of CPT-11 infusion. Delayed-type diarrhea was treated with loperamide (4 mg), followed by 2 mg every 2 hours for a 12-hour time period after the last liquid stool. Frequent sampling was performed before dosing and at approximately 0, 0.5, 1.5, 1.67, 1.83, 2, 2.5, 3.5, 4.5, 5, 5.5, 6.5, 8, 12, 25.5, 49, and 56 hours. Venous blood was drawn from the arm opposite the one used for infusion, and plasma was separated by centrifugation (3,000 x g for 5 minutes at 4°C). Plasma samples were stored at -80°C and analyzed for the lactone and total drug forms of CPT-11 and SN-38 and for the total drug forms only of APC, NPC, and SN-38G by using reversed-phase high-performance liquid chromatography with fluorescence detection, as described previously.15 Because of limited sample supply, concentrations could not be determined for all metabolites in all samples.
PK Modeling For all metabolites except SN-38G, we tested whether the concentration-time data were best described by formation from CPT-11 lactone, CPT-11 carboxylate, or a combination of these two. For SN-38G, models with formation from SN-38 lactone, SN-38 carboxylate, or both were tested. For each model, we tested whether the formation of metabolites was proportional to the dose, which is likely to be the case for a major metabolite, or whether it was proportional to the AUC of CPT-11, which is more likely to be the case for a minor metabolite. For the former, metabolite disposition parameters were expressed as ratios with the fraction of the dose metabolized to the particular metabolite. For the latter, metabolite parameters were expressed as ratios with the CL associated with formation of the metabolite in question (CLf). The individual CPT-11 lactone or carboxylate concentration-time profile, or both, from step 1 was used as the input for metabolite formation. Models based on lactone and carboxylate interconversion were simultaneously developed for SN-38 lactone and total concentrations (step 2), and then a model for SN-38G was developed, with individual parameters of SN-38 lactone and carboxylate from the final model of step 2 being fixed (step 3). As for CPT-11, the total concentrations of SN-38 were assumed to be the sum of lactone and carboxylate concentrations. Models containing an enterohepatic-cycle component were tested to describe SN-38 and SN-38G data. One strategy to do this was by presuming an extra biliary compartment to store part of the eliminated SN-38G; after a certain (estimated) time period, stored SN-38G would be released to another extra compartment (intestine) to be deconjugated to SN-38. Another model, assuming that an oral dose was given to generate rebound concentrations of SN-38, was tested for improvement of the description of the data. Finally, models for APC (step 4) and NPC (step 5) were developed. Candidate covariate relations for covariate models were built on the basis of individual parameters from the basic model by using generalized additive models.16 The covariates that resulted in a significant decrease in the Akaike information criterion were introduced into the model and tested. The covariates considered were age (median, 54 years; range, 36 to 71 years), sex (24 women and 46 men), and body-surface area (BSA; median, 1.86 m2; range, 1.35 to 2.5 m2). The models were fitted to the data from all individuals simultaneously by using NONMEM VI (University of California, San Francisco, CA) with first-order conditional estimation with interaction.17 The parameter for a specific subject (Pi) can be described by equation 1:
where Ppop is the parameter for a typical individual and In mixed-effect models, the residual error is the difference between the observed concentration (Cobs) and the predicted value (Cpred) by Pi. The residual error model was characterized by both additive and proportional components:
where
The model selection was guided by the decrease in the objection function value (OFV; -2 x log likelihood), as well as by using graphical goodness-of-fit analysis with Xpose 3.0 (Uppsala University, Uppsala, Sweden).18 To statistically distinguish between hierarchical models, the difference in the OFV was used because this difference is approximately
Forty-six male and 24 female cancer patients received CPT-11 as a 90-minute intravenous infusion (range, 1.3 to 1.9 hours) at doses ranging from 175 to 300 mg/m2. The predominant tumor types were colorectal cancer (n = 38), adenocarcinoma of unknown primary origin (n = 8), head and neck cancer (n = 5), and non–small-cell lung cancer (n = 4). Sixteen patients who received a second course of CPT-11 were pharmacokinetically studied, and the median time interval between two doses was 23 days (range, 11 to 38 days). The observed concentration-time profiles of CPT-11 and its four metabolites are presented in Fig 1, and all concentration units are nanograms per milliliter. The principal components of the model that resulted from the analysis are presented in Fig 2. Overall, CPT-11 carboxylate concentrations were higher than those of CPT-11 lactone, whereas concentrations of SN-38 carboxylate were lower than those of the lactone form. Both SN-38G and APC plasma concentrations were relatively high, whereas those of NPC were low.
The best model to describe CPT-11 lactone data alone was a three-compartment model with CL estimated to be 107 L/h (57.5 L/h/m2; step 0). In the joint model for CPT-11 lactone and carboxylate forms (step 1), disposition could be characterized with a three- and two-compartment model for CPT-11 lactone and carboxylate, respectively (Fig 3). The model with interconversion between lactone and carboxylate in the central compartments, as well as in the peripheral compartments, provides the best model for both the lactone and total forms of CPT-11. The intercompartmental CL and volume of distribution of the peripheral compartment for CPT-11 carboxylate were estimated to be small (0.0009 L/h and 0.01 L, respectively), but the OFV decreased by more than 1,000 compared with a one-compartment model for CPT-11 carboxylate. A re-parameterization, using rate constants between the central and peripheral compartment of the carboxylate, was applied for the CPT-11 model. The rate constant from central to peripheral of CPT-11 carboxylate was close to 0, according to the estimates of CL and volume of distribution, so this rate constant was fixed at 0, and the volume of distribution in the peripheral compartment was (arbitrarily) fixed to the corresponding value for the lactone in the final model with re-parameterization to the rate constant. Such a model predicted that CPT-11 carboxylate would not have multicompartmental characteristics were it not formed peripherally from the lactone form. However, because the mass flow of carboxylate is unidirectional from the peripheral to the central compartment, there is no information (or effect on the predictions) on the size of the peripheral carboxylate compartment. The population CL (12.3 L/h) and the steady-state volume of distribution (78 L, excluding peripherally formed carboxylate) of the carboxylate form were six-fold smaller than those of the lactone form (Table 1). The interindividual variability for parameters of CPT-11 lactone was generally high, with post hoc estimates of CL ranging from 24.8 to 149.9 L/h for the lactone form and from 6.6 to 19.5 L/h for the carboxylate form. BSA was the only significant covariate included in the model and had a decrease in OFV of 26.99 compared with the basic model. For a typical individual with a BSA of 1.86 m2, the CL and steady-state volume of distribution of CPT-11 lactone were 39.9 L/h/m2 and 239 L/m2, respectively.
SN-38 concentrations were best described by a two-compartment model for the lactone form and a one-compartment model for the carboxylate form, where the formation occurred from CPT-11 lactone in the central compartment to SN-38 lactone in the central compartment (Fig 4). In the model, SN-38 lactone formation was better described as proportional to the dose of CPT-11, rather than proportional to the AUC of CPT-11 lactone. Unlike CPT-11, SN-38 lactone and carboxylate forms had similar CL values, whereas, as for CPT-11, the lactone form had more extensive tissue distribution (Table 2). A one-compartment model, with formation from SN-38 lactone, adequately described the SN-38G data (Fig 5). SN-38G formation was better described as proportional to the dose of CPT-11 than to the AUC of SN-38 lactone. Both SN-38 and SN-38G had substantial formation variability. In the most successful model, SN-38G was formed out of SN-38 lactone (Fig 2 and Table 2). A relatively high interindividual variability was found for the disposition parameters and formation variability of SN-38 lactone and carboxylate and SN-38G (Table 2). Rebound concentrations of SN-38 and SN-38G were observed in some subjects, but the models with an enterohepatic recycling component were unsuccessful, possibly because of a lack of information of the recycling process. No significant covariate relations were identified for SN-38 or SN-38G.
A two-compartment model best described the total concentration data of APC with formation from CPT-11 carboxylate (Fig 6). Formation was better described as proportional to the AUC of CPT-11 carboxylate rather than the CPT-11 dose. Age was found to be a statistically significant covariate for the CL of APC. The typical CL ratio (CL/CLf) was 2.62 at an age of 55 years (Table 3), with a change of 1.4% per year. The only interindividual variability component was in the fraction forming APC, which was estimated to be 48%.
A two-compartment model with formation from CPT-11 lactone best described the concentration-time profiles of NPC (Fig 7). Formation was better described as being proportional to the AUC of CPT-11 lactone rather than to the CPT-11 dose. The interindividual variability in CL was 110%; this might be due to one individual’s having much higher NPC concentrations as compared with other individuals (2.2 to 11.7 times higher). In an analysis without that individual, the variability decreased to 43%. Considering the large effect of this individual on the variability component, final parameters of NPC are listed without this patient (Table 3). No statistically significant covariate relations were found for NPC.
Finally, the typical values of parameters for CPT-11, SN-38, SN-38G, APC, or NPC (Tables 1 to 3) were used in a simulation for a typical individual with a BSA of 1.86 m2 receiving a 1-hour infusion at a standard dose of 350 mg/m2. The simulated concentration-time profiles are presented in Fig 8. The terminal half-lives based on this simulation were 18.3, 18.1, 24.2, 24.2, 24.2, 18.3, and 33.3 hours for CPT-11 lactone, CPT-11 total, SN-38 lactone, SN-38 total, SN-38G, APC, and NPC, respectively. Of the dose administered, 74% was eliminated as CPT-11 lactone and 26% as CPT-11 carboxylate.
The clinical PK of CPT-11 has been extensively reported on in the literature.9,10,14 This investigation may add to that knowledge because (1) it is the first model-based analysis that takes into account the interconversion between lactone and carboxylate forms, (2) it reports more extensively on the PK of CPT-11 metabolites, and (3) the database is substantially larger than the ones used in previous reports. In addition, we introduce parameterizations of population PK models that allow additional information compared with standard models to be extracted from metabolite data. The CL estimate of 107 L/h (57.5 L/h/m2) in the analysis of the lactone form of CPT-11 that ignores the carboxylate interconversion (step 0) is in good agreement with previously reported values from similar analyses (39 to 75.1 L/h/m2).8,12,19 Similarly, the steady-state volume of distribution estimate of 722 L (388 L/m2) is in good agreement with previously reported values8 of 601 to 871 L but is somewhat larger than a reported value12 of 263 L/m2. Also, the full model, including conversion between lactone and carboxylate, predicts a similar value of CL (100 L/h; see Appendix [available online at www.jco.org]). As mentioned previously, CPT-11 and its metabolites contain a lactone ring, which undergoes a pH-dependent equilibrium with the carboxylate form.20 At physiologic pH, the carboxylate form of CPT-11 dominates in plasma. However, only the lactone form has antitumor activity.7 Therefore, it is of interest to differentiate the PK of the lactone form from the total drug form (ie, lactone plus carboxylate) of CPT-11. From the model that considers the lactone-carboxylate interconversion, a relatively rapid interconversion of CPT-11 lactone to carboxylate was found with a half-life of 14 minutes, which is close to the previously published value of 9.4 minutes.12 Population estimates of CL and steady-state volume of distribution of CPT-11 lactone were 39.9 L/h/m2 and 239 L/m2, respectively. The CL of CPT-11 lactone was six times higher than that of the carboxylate form. Published CL values of CPT-11 total are in the range of 12 to 24 L/h/m2 during short infusions (30 to 90 minutes).8,9,21 Our model predicts a CL of 18 L/h/m2 for total CPT-11 (see Appendix). The difference between lactone and total forms in CL may partly be explained by a lower distribution of the carboxylate form into the liver. The analysis also suggests a different metabolic pathway for CPT-11 carboxylate, with formation of APC while SN-38 and NPC are formed from CPT-11 lactone. CPT-11 lactone displayed extensive tissue distribution, and it was found that the rate constants between the central and peripheral compartments of CPT-11 carboxylate were much smaller than the interconversion rate constants from lactone to carboxylate between peripheral compartments, implying local conversion of CPT-11. CPT-11 is extensively metabolized to its active metabolite SN-38 by the carboxylesterase enzyme system,14,22 and the anticancer efficacy of SN-38 is far greater than the parent drug in vitro.23 Therefore, it is important to understand the PK of SN-38, especially for its active lactone form. During the model building for SN-38, the model with hydrolysis from CPT-11 lactone and carboxylate forms to the corresponding forms of SN-38 was tested, and it seemed that the model with only transformation between lactone forms performed best (final model). When the values of parameters were compared, the interconversion rate constant from SN-38 lactone to carboxylate (0.319/h; Table 2) was larger than the elimination rate constant of CPT-11 carboxylate (0.158/h, calculated from the CL of CPT-11 carboxylate and the volume of distribution of CPT-11 carboxylate in compartment 1, Table 1). This lends further support to the supposition that SN-38 carboxylate is formed by hydrolysis (lactone to carboxylate) and not through carboxylesterase-mediated metabolism from CPT-11 carboxylate. It has been reported that in vitro the steady-state formation rates of SN-38 by CPT-11 lactone are two times higher than those through CPT-11 carboxylate.24 Similarly, the parameter estimates from this modeling analysis indicated that the interconversion rate constant for lactonization (carboxylate to lactone) was 2.6-fold higher than that of hydrolysis (Table 2). The reason might be that SN-38 lactone is more tightly bound to human serum albumin than the carboxylate form, so the dynamic equilibrium is preferential toward the lactone form.25 This could explain the in vivo observations that the lactone form of SN-38 was the dominant form in patient plasma in our study and the earlier investigation by Rivory et al.12 From modeling, it was found that SN-38 formation was proportional to the dose of CPT-11, suggesting that SN-38 is a major metabolite. The fact that SN-38 disposition parameters were relatively high may suggest otherwise, but these high values could also be a consequence of a sequential metabolism of SN-38 to SN-38G in the liver. SN-38 can be further converted into SN-38G by hepatic uridine diphosphate glucuronyltransferase,3,4 and the plasma concentrations of this glucuronide compound were relatively high. It has been shown that the AUC ratio of SN-38G to SN-38 ranges from 4.5 to 32.8 SN-38G had the highest plasma concentrations of all metabolites. Evidence that SN-38G is the result of a major pathway of CPT-11 elimination was also indicated by the fact that the model assuming SN-38 and SN-38G was best related to dose. Large interindividual variability for parameters of CPT-11 lactone and SN-38 lactone was found in this study. This probably indicates that a large variability in carboxylesterase expression and activity exists between individuals and also indicates that variability in interconversion between lactone and carboxylate forms may partly contribute to the overall interindividual variability of these parameters.14,26 During the modeling, no significant covariates were found, except for BSA in the case of CPT-11 and age in the case of APC. This is consistent with previous observations from phase I and II clinical trials indicating that the CL of CPT-11 or the formation ratio of SN-38 and SN-38G is not significantly correlated with age, sex, serum creatinine level, transaminase level, alkaline phosphatase level, or the presence of liver metastases.27 Both APC and NPC total concentration-time profiles could be best described by two-compartment models. The model predicted that the metabolic pathway of CPT-11 to APC was through the carboxylate form. The interindividual variability in exposure to APC suggests that the differences in metabolism and formation between patients are the main source of variability for APC PK. Unlike APC, NPC was predicted to be mainly formed from CPT-11 lactone, and no formation variability was needed. It has been found in vivo8 that NPC is a minor plasma metabolite of the parent drug, which contrasts with in vitro results in which NPC was a major metabolite.6 An explanation for this apparent contra- diction could be the fact that NPC is subject to conversion to SN-38 by plasma carboxylesterases.6,14,28 This alternative metabolic pathway might partly explain the high interindividual variability in NPC PK. In summary, we built population PK models to adequately describe plasma data of CPT-11 and its currently known metabolites, including the lactone-carboxylate interconversion. These data not only increase our knowledge to better understand the clinical PK of this drug but also may prove useful in predicting the PK of all characterized metabolites and interconversion products after various administration regimens of CPT-11.
APPENDIX Compartments are numbered from 1 to 5 in the following order with regard to CPT-11: lactone central; lactone peripheral 1; carboxylate central; carboxylate peripheral; and lactone peripheral 2. Deriving the equation to calculate CPT-11 lactone clearance (CLL) considering interconversion between lactone and carboxylate forms. The relationship between these two forms is presented in Fig 1A. The amount (A) of change in each compartment is described by equations 1 to 5:
where R0 is the infusion rate and k is the rate constant. The Arabic numbers represent the compartmental numbers. At steady state (ss), the amount in each compartment is derived according to equations 6 to 10:
If equations 6, 7, 8, 9, and 10 are rearranged, lactone concentration at steady state can be expressed as
The CLL is expressed as the ratio of R0 and C(1)ss. Therefore, CLL (taking into consideration the equilibrium with the carboxylate form) can be calculated by using equation 12, where V1 is the volume of distribution in the central compartment of the lactone form (compartment 1):
Deriving the equation to estimate the clearance of CPT-11 total forms (CLT), considering the interconversions between lactone and carboxylate forms. The steady-state plasma concentration of CPT-11 total (CT,ss) is the sum of lactone (C(1)ss) and carboxylate (C(3)ss) forms. Combined with equation 8, CT,ss can be expressed as
where V3 is the volume of distribution in the central compartment of the carboxylate form (compartment 3). The total clearance of CPT-11 lactone is the ratio of infusion rate and CT,ss. Therefore, CLT can be derived from equations 12 and 13:
Supported by the Swedish Cancer Society.
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6. Dodds HM, Haaz MC, Riou JF, et al: Identification of a new metabolite of CPT-11 (irinotecan): Pharmacological properties and activation to SN-38. J Pharmacol Exp Ther 286: 578-583, 1998 7. Hertzberg RP, Caranfa MJ, Holden KG, et al: Modification of the hydroxy lactone ring of camptothecin: Inhibition of mammalian topoisomerase I and biological activity. J Med Chem 32: 715-720, 1989[CrossRef][Medline]
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14. Mathijssen RH, van Alphen RJ, Verweij J, et al: Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7: 2182-2194, 2001 15. de Bruijn P, Verweij J, Loos WJ, et al: Determination of irinotecan (CPT-11) and its active metabolite SN-38 in human plasma by reversed-phase high-performance liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci Appl 698: 277-285, 1997[CrossRef][Medline] 16. Mandema JW, Verotta D, Sheiner LB: Building population pharmacokinetic–pharmacodynamic models: I. Models for covariate effects. J Pharmacokinet Biopharm 20: 511-528, 1992[CrossRef][Medline] 17. Beal SL, Sheiner LB: NONMEM Users’ Guides. San Francisco CA, NONMEM Project Group, University of California at San Francisco, 1992 18. Jonsson EN, Karlsson MO: Xpose: An S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58: 51-64, 1999[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
i is a symmetrically distributed zero-mean variable with SD 
. Several factors may cause interindividual correlations between all disposition parameters of a metabolite, but a major cause for such correlations may be interindividual variability in the fraction of the dose forming the metabolite. We chose to parameterize the models so that any such correlation was expressed as variability in the fraction of dose forming the metabolite, because this may aid interpretation and simplify modeling and have no detrimental effect on the fit of the models to the data. 
1 and 
1 and 
2 distributed. A significance level of P < .001 was used; this corresponded to a difference in OFV of 10.8 for 1 df. Parameter uncertainty was expressed as RSE%, which is the estimate of SE obtained as part of the standard NONMEM output, divided by the parameter value. 
