Model-based approach for methoxy polyethylene glycol-epoetin beta drug development in paediatric patients with anaemia of chronic kidney disease.

AIMS: Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter-acting erythropoiesis-stimulating agents up to three times weekly can be switched to once-monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model-based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan. METHODS: Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model-based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real-world data. RESULTS: Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL-1 ) and C.E.R.A. doses (median and 95% prediction interval 105 [72, 159] µg) 20 weeks after switching to subcutaneous C.E.R.A. were confirmed by observed real-world data from International Pediatric Dialysis Network registries (mean Hb was 10.8 g dL-1 and median C.E.R.A. dose was 100 µg). CONCLUSIONS: These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.

Generics in transplantation medicine: Randomized comparison of innovator and substitution products containing mycophenolate mofetil
.

OBJECTIVE: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. MATERIALS AND METHODS: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (Cmax) and areas under plasma concentration-time curves were calculated. RESULTS: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 - 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. CONCLUSION: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.

Development of a physiologically based pharmacokinetic model for mefloquine and its application alongside a clinical effectiveness model to select an optimal dose for prevention of malaria in young Caucasian children.

AIMS: To predict the optimal chemoprophylactic dose of mefloquine in infants of 5-10 kg using physiologically based pharmacokinetic (PBPK) and clinical effectiveness models. METHODS: The PBPK model was developed in Simcyp version 14.1 and verified against clinical pharmacokinetic data in adults; the final model, accounting for developmental physiology and enzyme ontogeny was then applied in the paediatric population. The clinical effectiveness model utilized real-world chemoprophylaxis data with stratification of output by age and including infant data from the UK population. RESULTS: PBPK simulations in infant populations depend on the assumed fraction of mefloquine metabolized by CYP3A4 (0.47, 0.95) and on the associated CYP3A4 ontogeny (Salem, Upreti). However, all scenarios suggest that a dose of 62.5 mg weekly achieves or exceeds the exposure in adults following a 250 mg weekly dose and results in a minimum plasma concentration of 620 ng ml-1 , which is considered necessary to achieve 95% prophylactic efficacy. The clinical effectiveness model predicts a 96% protective efficacy from mefloquine chemoprophylaxis at 62.5 mg weekly. CONCLUSIONS: The PBPK and clinical effectiveness models are mutually supportive and suggest a prophylactic dose of 62.5 mg weekly in the Caucasian 5-10 kg infant population travelling to endemic countries. This dual approach offers a novel route to dose selection in a vulnerable population, where clinical trials would be difficult to conduct.

Pediatric Dosing of Ganciclovir and Valganciclovir: How Model-Based Simulations Can Prevent Underexposure and Potential Treatment Failure.

Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus (CMV) infection but various dosing regimens are used in medical practice. Population pharmacokinetic (PopPK) model-based simulations were used to propose a new ganciclovir pediatric dosing algorithm for regulatory review and to evaluate the approved valganciclovir pediatric dosing algorithm against published dosing recommendations derived from quantitative approaches. Oral valganciclovir (mg = 7 × body surface area (BSA) × creatinine clearance according to the Schwarz formula (CrCLS) daily) and i.v. ganciclovir (mg = 3 × BSA × CrCLS daily) are effective in reaching ganciclovir target exposure for the prevention of CMV (area under the concentration-time curve (AUC)0-24 40-60 µg âˆ™ hour/mL) in most pediatric patients across the full pediatric age range. In contrast, ganciclovir and valganciclovir dosing based on body weight, as commonly used in medical practice, leads to underexposure, particularly in younger pediatric patients. This example shows that model-based dosing algorithms built on clinical pharmacology and implemented using good modeling practice can prevent underexposure and reduce the risk of treatment failure in pediatric patients.

Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.

The main purpose of dose-escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose-escalation designs that incorporate both the dose-limiting events and dose-limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose-escalation strategies. The first type of procedures, called "single objective," aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called "dual objective," aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose-escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual-objective designs give better results in terms of identifying the 2 real target doses compared to the single-objective designs.

Bayesian adaptive dose-escalation procedures for binary and continuous responses utilizing a gain function.

One of the main aims of early phase clinical trials is to identify a safe dose with an indication of therapeutic benefit to administer to subjects in further studies. Ideally therefore, dose-limiting events (DLEs) and responses indicative of efficacy should be considered in the dose-escalation procedure. Several methods have been suggested for incorporating both DLEs and efficacy responses in early phase dose-escalation trials. In this paper, we describe and evaluate a Bayesian adaptive approach based on one binary response (occurrence of a DLE) and one continuous response (a measure of potential efficacy) per subject. A logistic regression and a linear log-log relationship are used respectively to model the binary DLEs and the continuous efficacy responses. A gain function concerning both the DLEs and efficacy responses is used to determine the dose to administer to the next cohort of subjects. Stopping rules are proposed to enable efficient decision making. Simulation results shows that our approach performs better than taking account of DLE responses alone. To assess the robustness of the approach, scenarios where the efficacy responses of subjects are generated from an Emax model, but modelled by the linear log-log model are also considered. This evaluation shows that the simpler log-log model leads to robust recommendations even under this model showing that it is a useful approximation to the difficulty in estimating Emax model. Additionally, we find comparable performance to alternative approaches using efficacy and safety for dose-finding.

Bayesian adaptive designs in single ascending dose trials in healthy volunteers.

AIM: Recent publications indicate a strong interest in applying Bayesian adaptive designs in first time in humans (FTIH) studies outside of oncology. The objective of the present work was to assess the performance of a new approach that includes Bayesian adaptive design in single ascending dose (SAD) trials conducted in healthy volunteers, in comparison with a more traditional approach. METHODS: A trial simulation approach was used and seven different scenarios of dose-response were tested. RESULTS: The new approach provided less biased estimates of maximum tolerated dose (MTD). In all scenarios, the number of subjects needed to define a MTD was lower with the new approach than with the traditional approach. With respect to duration of the trials, the two approaches were comparable. In all scenarios, the number of subjects exposed to a dose greater than the actual MTD was lower with the new approach than with the traditional approach. CONCLUSIONS: The new approach with Bayesian adaptive design shows a very good performance in the estimation of MTD and in reducing the total number of healthy subjects. It also reduces the number of subjects exposed to doses greater than the actual MTD.

Effect of hemodialysis and hemofiltration on plasma C.E.R.A. concentrations.

C.E.R.A., a continuous erythropoietin receptor activator, is a long-acting erythropoiesis-stimulating agent approved for the treatment of anemia in patients with chronic kidney disease. Although the large molecular weight and the carbohydrate chain make it unlikely that C.E.R.A. could be removed during hemodialysis or hemofiltration, no such data have been published. In vitro studies were performed to assess the removal of C.E.R.A. during hemodialysis and hemofiltration, using both low-flux and high-flux membranes and parameters very similar to those used in clinical practice. Clinical pharmacokinetic studies of plasma C.E.R.A. concentrations in patients undergoing hemodialysis were also performed following subcutaneous injection of C.E.R.A. In the in vitro studies, plasma C.E.R.A. concentrations were not significantly different from baseline values in the primed blood reservoir over a 4-hour period during hemodialysis (P = 0.12). C.E.R.A. concentrations in the plasma obtained from the venous end of the hemofilter increased proportionally with the plasma total protein concentrations, reflecting the consequence of hemoconcentration and suggesting that C.E.R.A and plasma total proteins were retained by hemofiltration membranes to a similar degree. These in vitro studies showed that C.E.R.A. was not removed by simulated hemodialysis or hemofiltration either via transmembrane transport or adsorption to the membrane. The results were corroborated by the clinical pharmacokinetic data, which showed no detectable changes in plasma C.E.R.A. concentrations during hemodialysis using either low-flux or high-flux dialyzers. These results suggest that C.E.R.A. can be administered to patients at any time during hemodialysis or hemofiltration without appreciable loss in the extracorporeal circuit.

Population pharmacokinetic/pharmacodynamic model for C.E.R.A. in both ESA-naive and ESA-treated chronic kidney disease patients with renal anemia.

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) patients. Population models were specified to describe C.E.R.A. (PK) and hemoglobin (PD) concentrations over time, using data from 3 phase III, open-label, randomized, parallel-group, multicenter studies that examined IV or SC C.E.R.A. administration Q2W and Q4W in erythropoiesis-stimulating agent (ESA)-naive and ESA-treated patients. C.E.R.A. PK was described by a 1-compartment model: drug clearance = 0.75 L/d, volume of distribution = 4.72 L, and half-life = 105 hours in accordance with previous reported values. The PD model, a life span sequential PK/PD model, adequately described hemoglobin data. Dosing schedule, administration route, and study type did not affect drug-related PD parameters or system-specific parameters (eg, red blood cell life span). This model adequately described C.E.R.A.'s PK and PD properties according to C.E.R.A. posology, thus permitting simulations exploring alternative drug administration scenarios. It supports use of C.E.R.A. IV and SC; Q2W for anemia correction in ESA-Naïve CKD patients and monthly administration in the hemoglobin maintenance phase.

The effect of severe hepatic impairment on the pharmacokinetics and haematological response of C.E.R.A.

AIM: To examine the effect of severe hepatic impairment (HI) on the pharmacokinetics (PK) and pharmacodynamics (PD) of the continuous erythropoietin receptor activator, C.E.R.A. METHODS: A non-randomised, multicentre, single-dose, open-label study in patients with HI (n=12) and healthy subjects (n=12). After 2 weeks of screening, participants received a single intravenous dose of C.E.R.A. (200 mug), and were then followed for approximately 8 weeks. The area under the concentration-time curve (AUC) from drug administration to last measurable concentration (AUC(last)), and maximum C.E.R.A. concentration (C(max)) were calculated to assess PK. The baseline-corrected area under the effect curve over 22 days (AUE(corr)) for reticulocyte count was the primary PD parameter. RESULTS: The PK profile was similar in patients and healthy subjects (AUC(last): 6678 vs 6985 ng*h/mL; C(max): 63 vs 75 ng/mL) C.E.R.A. produced a sustained erythropoietic response in bothgroups, with increases in reticulocyte counts peaking 7-9 days post-dose and returning to baseline by Day 22. Although mean AUE(corr) was 64% lower in patients, this may have been an artefact of higher baseline reticulocyte counts. Lower reticulocyte responses in patients did not translate into lower responses for haemoglobin, haematocrit or erythrocytes, suggesting that HI had no clinically relevant effect on the PD of C.E.R.A. C.E.R.A. was well tolerated. Four AEs (none considered drug related) were reported in three patients (mild myocardial ischaemia; mild pyrexia and liver transplant; severe bacterial peritonitis [serious AE]); no AEs were reported in healthy subjects. CONCLUSIONS: Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.

Subcutaneous injection pain with C.E.R.A., a continuous erythropoietin receptor activator, compared with darbepoetin alfa.

OBJECTIVE: This study assessed injection site pain following subcutaneous (SC) administration with a continuous erythropoietin receptor activator (C.E.R.A.), compared with darbepoetin alfa in healthy adults. METHODS: In a randomized, placebo-controlled, single-centre, single-blind, three-way crossover study, subjects received one of six treatment sequences (ABC/ACB/BAC/BCA/CBA/CAB) involving SC injection of (A) C.E.R.A. 50 microg, (B) darbepoetin alfa 50 microg, or (C) placebo on days 1, 29, and 57. An initial pilot phase (n = 12) was used to determine the sample size for the confirmatory phase (n = 72), and data were combined for the final analysis (n = 84). MAIN OUTCOME MEASURES: The primary endpoint was pain on the 100 mm visual analog scale (VAS) immediately after dosing. Secondary endpoints included VAS at 1 hour after dosing and pain on the six-point verbal rating scale (VRS) immediately and at 1 hour after dosing. RESULTS: C.E.R.A. was associated with significantly less pain immediately after SC injection compared with darbepoetin alfa: least squares mean VAS 21.5 (95% confidence interval [CI]: 17.5, 25.5) versus 33.4 (95% CI: 28.4, 38.4) (p < 0.0001). Incidence of pain on the VRS was lower with C.E.R.A. compared with darbepoetin alfa immediately after dosing (p < 0.0001). One hour after administration, most subjects had no VRS pain. A study limitation is the small sample size and the findings need to be confirmed in a large trial of chronic kidney disease patients. CONCLUSIONS: SC injection with C.E.R.A. is significantly less painful than SC darbepoetin alfa in healthy adults. Treatment of anemia in chronic kidney disease with SC injection of C.E.R.A. may provide a lower pain burden compared with darbepoetin alfa.

Pharmacokinetic and pharmacodynamic properties of methoxy polyethylene glycol-epoetin beta are unaffected by the site of subcutaneous administration.

C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, differs from traditional erythropoiesis-stimulating agents in its pharmacokinetic and receptor binding properties. This phase I, randomized, open-label, single-center, single-dose, 3-way crossover study in 42 healthy volunteers compared the pharmacokinetic and pharmacodynamic profile of C.E.R.A. 3.0 microg/kg after subcutaneous injection into the abdomen, arm, or thigh. The pharmacokinetic profile was similar at all 3 injection sites, with a prolonged apparent elimination half-life from 160 to 164 hours, area under the concentration-time curve from 4088 to 4323 ng.h/mL, and clearance/bioavailability from 0.64 to 0.68 mL/h/kg. C.E.R.A. produced a sustained erythropoietic response, and the pharmacodynamic profile (area under the reticulocyte count-time curve and maximum increase in reticulocyte count) was similar for all sites. C.E.R.A. was generally well tolerated, regardless of the administration site. This study suggests that C.E.R.A. has the potential to offer a choice of injection sites in clinical practice. The long half-life may permit effective anemia management with extended dosing intervals. Phase III clinical studies support the role of C.E.R.A. in managing anemia in patients with chronic kidney disease.

C.E.R.A.: pharmacodynamics, pharmacokinetics and efficacy in patients with chronic kidney disease.

C.E.R.A., a continuous erythropoietin receptor activator, has been developed for the treatment of anaemia in patients with chronic kidney disease. Compared with other erythropoiesis-stimulating agents, C.E.R.A. has a unique pharmacological profile, including a longer elimination half-life and slower clearance rate. This allows C.E.R.A. to be administered at extended intervals up to once every month. Phase III clinical trials have shown that C.E.R.A. once every 2 weeks corrects anaemia in erythropoiesis-stimulating agent-naive patients who are on or are not on dialysis, whereas once-monthly C.E.R.A. maintains stable haemoglobin levels when patients are directly converted from more frequent epoetin or darbepoetin alpha administration. C.E.R.A. is well tolerated. This review summarises clinical data on C.E.R.A. and discusses the potential effect of this novel agent on clinical practice.

Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease.

Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaïve patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD.

Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer.

PURPOSE: Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin. PATIENTS AND METHODS: Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61. RESULTS: During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC(0-infinity)) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t(1/2); 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance. CONCLUSION: There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly.

Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancer.

BACKGROUND: Capecitabine (Xeloda) is a novel, oral fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue via a three-step enzymatic cascade. PURPOSE: The objective of this study was to compare the pharmacokinetics of capecitabine and its metabolites in Japanese and Caucasian cancer patients. METHODS: The study included 20 Japanese and 24 Caucasian patients with breast cancer. All patients received oral capecitabine 825 mg/m(2) twice daily for 14 days, except for study day 1 when only the morning dose was administered. On study days 1 and 14, blood and urine samples were collected after administration of the first dose and at steady state for the evaluation of the pharmacokinetics of capecitabine and its metabolites. The primary pharmacokinetic parameter was AUC(0-infinity ) of 5'-deoxy-5-fluorouridine (5'-DFUR) on day 14. The pharmacokinetic parameters in Japanese and Caucasian patients were compared using an ANOVA with calculation of the 90% confidence interval (CI) for the ratio of the geometric means. RESULTS: Statistical analysis showed equivalence in the AUC of 5'-DFUR on day 14 with a ratio of 1.01 (90% CI 0.85-1.21). Similarly, no relevant influence of race on the pharmacokinetics of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), or 5-FU was observed. Systemic exposure to alpha-fluoro-beta-alanine (FBAL) was higher in Caucasian than in Japanese patients. On study day 14, both the AUC and the maximum plasma concentration (C(max)) of FBAL were increased by 47% and 33% in Caucasian patients and Japanese patients, respectively. CONCLUSIONS: No clinically relevant differences in the pharmacokinetics of capecitabine and its key metabolites 5'-DFUR, 5'-DFCR, and 5-FU were found between Japanese and Caucasian patients. Plasma concentrations of FBAL were higher in Caucasian than in Japanese patients but this difference is not clinically relevant as FBAL has no antiproliferative activity and systemic exposure to FBAL does not correlate with the tolerability of capecitabine.

Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients.

AIMS: To assess the relationship between systemic exposure to capecitabine metabolites and parameters of efficacy and safety in patients with advanced or metastatic colorectal cancer from two phase III studies. METHODS: Concentration-effect analyses were based on data from 481 patients (248 males, 193 females; age range 27-86 years) in two phase III studies. Plasma concentration-time data for 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU) and alpha-fluoro-beta-alanine (FBAL) were obtained from sparse blood samples collected within the time windows 0.5-1.5 h, 1.5-3.0 h, and 3.0-5.0 h after capecitabine administration (1250 mg m(-2)) on the first day of cycles 2 (day 22) and 4 (day 64), respectively. Systemic exposure based on plasma concentrations of capecitabine and its metabolites was determined using individual parameter estimates derived from a population pharmacokinetic model constructed for this purpose in NONMEM. Logistic regression analysis was conducted for selected safety parameters (all treatment-related grade 3-4 adverse events, treatment-related grade 3-4 diarrhoea, grade 3 hand-foot syndrome (HFS) and grade 3-4 hyperbilirubinaemia) and for tumour response. Cox regression analysis was used for the analysis of time-to-event data (time to disease progression and duration of survival). RESULTS: Statistically significant relationships between covariates and PK parameters were found as follows. A doubling of alkaline phosphatase activity was associated with a 11% decrease in 5-FU clearance and a 12% increase in its AUC. A 50% decrease in creatinine clearance was associated with a 35% decrease in FBAL clearance, a 53% increase in its AUC, a 24% decrease in its volume of distribution, and a 41% increase in its Cmax. A 30% increase in body surface was associated with a 24% increase in the volume of distribution of FBAL and a 19% decrease in its Cmax. There was a broad overlap in systemic drug exposure between patients regardless of the occurrence of treatment-related grade 3-4 adverse events or response to treatment, leading to weak relationships between systemic exposure to capecitabine metabolites and the safety and efficacy parameters. Of 42 concentration-effect relationships investigated, only five achieved statistical significance. Thus, we obtained a positive association between the AUC of FBAL and grade 3-4 diarrhoea (P = 0.035), a positive association between the AUC of 5-FU and grade 3-4 hyperbilirubinaemia (P = 0.025), a negative association between the Cmax of FBAL and grade 3-4 hyperbilirubinaemia (P = 0.014), a negative association between the AUC of 5-FU (in plasma) and time to disease progression (hazard ratio (HR) = 1.626, P = 0.0056), and a positive association between the Cmax of 5'-DFUR and survival (HR = 0.938, P = 0.0048). Additionally, there were inconsistencies when concentration-effect relationships were compared across the two studies. CONCLUSIONS: Systemic exposure to capecitabine and its metabolites in plasma is poorly predictive of safety and efficacy. The present results have no clinical implications for the use of capecitabine and argue against the value of therapeutic drug monitoring for dosage adjustment.

Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients.

PURPOSE: The primary objective of this study was to investigate the influence of renal impairment on the pharmacokinetics of capecitabine and its metabolites in cancer patients. Capecitabine (Xeloda) is an orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), which is preferentially activated to 5-fluorouracil (5-FU) in tumors. METHODS: A total of 27 patients were enrolled, of whom 24 were evaluable for pharmacokinetics (6 with normal renal function, 8 with mild, 6 with moderate, and 4 with severe renal impairment at baseline). Patients received capecitabine orally at the standard dosing regimen (1250 mg/m(2) capecitabine twice daily for 2 weeks followed by a 1-week rest period). On study days 1 and 14, blood samples were collected to evaluate the pharmacokinetics of capecitabine and its metabolites. The relationship between the area under the plasma concentration-time curve (AUC) and creatinine clearance (CL(CR)) was assessed by log-linear regression analysis. RESULTS: The primary pharmacokinetic parameter with respect to the effect of renal dysfunction was systemic exposure to 5'-DFUR, 5-FU and FBAL determined on study day 14. Renal impairment led to an increase in the systemic exposure to 5'-DFUR and FBAL (23% and 109% increase in AUC, respectively) for a 50% reduction in CL(CR). By contrast, renal impairment may lead to decreased exposure to 5'-DFCR. There was no evidence for an effect of renal impairment on systemic exposure to 5-FU or capecitabine. Renal impairment did not have a major effect on peak concentration (C(max)) or elimination half-life (t(1/2)) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU. However, in the case of FBAL, moderate or severe renal impairment caused up to a twofold increase in C(max) and prolongation of t(1/2). All patients with severe renal impairment (four patients) had drug-related grade 3 or 4 adverse-events (AEs) and serious AEs. Patients with moderate renal impairment experienced a similar number of grade 3 or 4 AEs (six of nine patients) but had a higher incidence of serious AEs (three of nine patients) when compared with those with normal renal function (four of six patients and one of six patients, respectively). A similar effect was seen in patients with mild renal dysfunction (grade 3 or 4 AEs in four of eight patients; serious AEs in three of eight patients). The relationship between systemic exposure to capecitabine or its metabolites and safety was investigated using logistic regression. This exploratory analysis showed a strong positive relationship between AUC of 5'-DFUR and treatment-related grade 3 or 4 AEs, whereas there was no relationship with exposure to capecitabine, 5'-DFCR, 5-FU or FBAL. CONCLUSIONS: Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5'-DFUR and FBAL. However, only the AUC of 5'-DFUR is correlated with safety. Based on the safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results from the present study support the recommendation that patients with moderate renal impairment should be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable to that in patients with normal renal function.

Estimating the starting dose for entry into humans: principles and practice.

BACKGROUND: Selection of the starting dose for the entry into humans (EIH) study is an essential first step in clinical drug development. OBJECTIVES: This paper is a review of different approaches that may be used to calculate the starting dose, presents the results of a current practice survey that reflect practice patterns at a large pharmaceutical company, and discusses selected topics related to the calculation of the starting dose. RESULTS: The methods used in the field of oncology for cytotoxic compounds are usually derived from a dose associated with some toxicity in animals multiplied by a safety factor. In therapeutic areas other than oncology, methods may be classified as four different approaches: (1) dose by factor methods that utilize the no observable adverse effect level (NOAEL) from pre-clinical toxicology studies multiplied by a safety factor; (2) the similar drug approach that may be used when clinical data are available for another compound of the same chemical class as the investigational drug; (3) the pharmacokinetically guided approach that uses systemic exposure rather than dose for the extrapolation from animal to man; and (4) the comparative approach that consists of utilizing two or more methods to estimate a starting dose and then critically comparing the results to arrive at the optimal starting dose. A "real-life" example illustrates the use of each method. Advantages, limitations, and underlying assumptions of each of the methods are discussed. The results of the survey showed that the pharmacokinetically guided approach is the most commonly used method, followed by dose by factor methods. CONCLUSION: The task of estimating the starting dose is moving beyond empirical methods to those that are increasingly more systematic and theory based.