Population pharmacokinetic (PPK) modeling and simulation-derived dosing of intravenous busulfan...
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CLINICALPHARMACOLOGY & TtIERAPEUTICS P66 American Societyfor Clinical Pharmacology and Therapeutics F~RU~Y2003 PIII-14 PHARMACOKINETICS OF A GLYBURIDE/METFORMIN COMBINATION TABLET IN CHILDREN AND ADOLESCENTS WITH TYPE 2 DIABETES. K. C. Turner, Ph~ M. Christensen, PharmD, J. D. Connor, MD, K. T. Moore, BA, X. Gao, PhD, S. R. Donahue, MD, Bristol-Myers Squibb Pharmaceutical Research Insti- tute, University of Tennessee, University of San Diego, Princeton, NJ. Purpose: To assess the pharmacokinetics (PK), safety, and toler- ability of a single glyburide/metformin combination (G/M) tablet in children and adolescents with type 2 diabetes and normal renal function. Methods: In an open-label, non-randomized study, children (10-12 years of age; 92 ± 34 kg) and adolescents (13-16 years of age; 100 + 19 kg) received a single oral 1.25 rag/250 mg G/M tablet 5 min prior to a standard low-fat breakfast. PK samples were collected for 24 h post-dose and assayed for glyburide and metformin plasma concentrations by a validated LC/MS/MS method. PK parameters were determined by non-compartmental analysis. Subjects were mon- itored closely for adverse events (AEs). Results: Glyburide Metformin Children Adolescents Children Adolescents Parameter (N=8) (N=20) (N=8) (N=20) Cmax [ng/mL] ~ 36,2 (50.6) 43.8 (38.7) 464 (23.7) 478 (32.2) AUC(INF) [tag'h/mL] ~ 159 (35.8) 171 (32.3) 2951 (21.8) 3011 (33.4) T-HALF [hlb 7.93 (5.17) 6.35 (3.07) 4.38 (0.81) 4.09 (0.57) geometric mean (%CV); b arithmetic mean (SD) There were no serious AEs or discontinuations due to AEs. Conclusions: The PK of both glyburide and mefformin in the 10-12 year old age group was similar to that in the 13-16 year old age group. A single oral 1.25 mg/250 mg G/M tablet was safe and well-tolerated in these pediatric subjects. PIII-15 LONG-TERM PHARMACOTHERAPY FOR WEIGHT LOSS IN PATIENTS WITH OBESITY. R. S. Padwal, MD, S. K. Li, MD, D. Lau, MD, University of Toronto, Sunnybrook and Women's College Hospital, University of Calgary, Toronto, Canada. Purpose: To systematically review the effectiveness and safety of approved anti-obesity medications for promoting weight loss in dou- ble blind, placebo-controlled randomized trials with follow-up peri- ods of one year or greater. Methods: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and Current Science Meta-register of Controlled Trials were searched. To identify unpublished studies, obesity experts and phar- maceutical companies were contacted. Abstracts and pseudo- randomized trials were not included. No language restriction was imposed. Results: Eight orlistat (n=4396) and 3 sibutramine (n=929) studies met the inclusion criteria. All patients received lifestyle modification. Attrition rates averaged 33% in the orlistat studies and 48% in the sibutramine studies. Compared to placebo, orlistat-treated patients displayed a 2.8% (95% CI: 2.2% to 3.5%) greater reduction in percentage of baseline body weight and patients on sibutramine, a 4-5.5% greater weight loss (p<0.05 for all three studies) after one year of follow-up. The number of patients achieving 10% or greater weight loss was 13% (95% CI: 9% to 17%) higher with orlistat and 15% (95% CI: 4% to 27%) higher with sibntramine compared to placebo. Orlistat caused increased GI side effects and sibutramine was associated with small increases in blood pressure. Conclusion: Orlistat and sibutramine are modestly effective in promoting weight loss, although a subset of patients may achieve greater benefit. PIII-16 LACK OF EFFECT OF APREPITANT ON DIGOXIN PHAR MACOKINETICS 1N HEALTHY SUBJECTS. Y. Lee, PhD, L. H. Oflowski, MS, N. Michiels, K. J. Petty, MD, PhD, M. R. Goldberg, MD, PhD, J. Dru, C. M. Chavez-Eng, M. Constanzer, G. Murphy, MD, K. Gottesdiener, MD, M. Hesney, MS, M. Feuring, M. Wehling, Merck & Co., Inc., lnstitut fur Klinische Phannakologie, West Point, PA. Aprepitant is a highly selective antagonist of the neurokinin-1 (NK-1) receptor that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be highly effective in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting (CINV). Since in clini- cal practice aprepitant might be coadministered with digoxin (a p-glycoprotein substrate) or other p-glycoprotein substrates, this study investigated whether aprepitant affects the plasma concentra- tions and urinary excretion of immunoreactive digoxin in healthy subjects. In a double-blind, placebo-controlled, randomized, two- period, crossover study, 12 subjects were dosed for 13 days in 2 separate periods. During both treatment periods (A and B), subjects received daily oral doses of digoxin 0,25 mg on Days 1 through 13. In Treatment A, subjects received a single oral dose of aprepitant 125 mg on Day 7 and single oral doses of aprepitant 80 rag/day on Days 8 through 11. In Treatment B, subjects received aprepitant placebo with digoxin. The geometric mean ratios (90% CI) for plasma AUCo-24 hr of immunoreactive digoxin (with/without aprepitant) were 0.99 (0,91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively. The geometric mean ratios (90% CI) for 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. In conclusion, the aprepitant dosing regimen for the prevention of CINV did not affect the pharmacokinefics of digoxin. This suggests that the aprepitant regimen for CINV is unlikely to produce clinically significant pharmacokinetic interactions with drugs that are substrates of the p-glycoprotein transporter. PIII-17 POPULATION PHARMACOKINETIC (PPK) MODELING AND SIMULATION-DERIVED DOSING OF INTRAVENOUS BUSULFAN (BUSULFEX) IN PEDIATRIC PATIENTS. B.P. Booth, PhD, A. Rahman, PhD, R. N. Dagher, MD, D. Griebel, MD, A. Lai, PhD, S. Lennon, D. Fuller, MD, J. V. Gobburu, PhD, FDA\CDER\OCPB, FDA\CDER\OND, CPKD Solutions, Orphan Medical, Inc., Rockville, MD. Purpose: There are varying approaches to dosing busulthn (Bu) in pediatric patients. The objective was to characterize the PK of Busulfex (IVBU) and provide pediatric dosing recommendations to consistently achieve appropriate systemic exposure (SE). Methods: Twenty-four pediatric patients (0.5 to t7y) were treated with IVBU Q.I.D. for 4 days. Starting doses were 1.0 or 0.8mg/kg for ages -<4y or >4y, respectively. Target SE was 900 - 1350 ~M.min. About 20 plasma samples per patient were collected over 4 days. PPK models were developed using NONMEM. Body weight (BW), age, gender, and body surface area (BSA) were explored for covariate effects and Monte Carlo simulations performed. Results: The PK of IVBU were described by a one-compartment model with clearance (CL) 3.37 ml/min/kg and volume of distribu- tion (V) of 0.64 L/kg. The terminal tl/2 was 2h. Simulations using various mg/m2 and mg/kg regimens indicated the best mg/kg regimen (using 2 dose levels) was similar to the best mg/m 2 regimen, and achieved the desired first dose SE in approximately 60% of pediatric patients. Conclusions: The PPK model adequately characterized the behav- ior of IVBU in pediatric patients. BW dosing was selected for clinical utility. This model suggests that patients ~< 12 kg should be dosed at 1.1 mg/kg, and those >12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment based on dose 1 may further improve therapeutic targeting.
Transcript of Population pharmacokinetic (PPK) modeling and simulation-derived dosing of intravenous busulfan...
CLINICAL PHARMACOLOGY & TtIERAPEUTICS
P66 American Society for Clinical Pharmacology and Therapeutics F~RU~Y2003
PIII-14 PHARMACOKINETICS OF A GLYBURIDE/METFORMIN
COMBINATION TABLET IN CHILDREN AND ADOLESCENTS WITH TYPE 2 DIABETES. K. C. Turner, P h ~ M. Christensen, PharmD, J. D. Connor, MD, K. T. Moore, BA, X. Gao, PhD, S. R. Donahue, MD, Bristol-Myers Squibb Pharmaceutical Research Insti- tute, University of Tennessee, University of San Diego, Princeton, NJ.
Purpose: To assess the pharmacokinetics (PK), safety, and toler- ability of a single glyburide/metformin combination (G/M) tablet in children and adolescents with type 2 diabetes and normal renal function.
Methods: In an open-label, non-randomized study, children (10-12 years of age; 92 ± 34 kg) and adolescents (13-16 years of age; 100 + 19 kg) received a single oral 1.25 rag/250 mg G/M tablet 5 min prior to a standard low-fat breakfast. PK samples were collected for 24 h post-dose and assayed for glyburide and metformin plasma concentrations by a validated LC/MS/MS method. PK parameters were determined by non-compartmental analysis. Subjects were mon- itored closely for adverse events (AEs).
Results:
Glyburide Metformin
Children Adolescents Children Adolescents Parameter (N=8) (N=20) (N=8) (N=20)
Cmax [ng/mL] ~ 36,2 (50.6) 43.8 (38.7) 464 (23.7) 478 (32.2) AUC(INF) [tag'h/mL] ~ 159 (35.8) 171 (32.3) 2951 (21.8) 3011 (33.4) T-HALF [hl b 7.93 (5.17) 6.35 (3.07) 4.38 (0.81) 4.09 (0.57)
geometric mean (%CV); b arithmetic mean (SD)
There were no serious AEs or discontinuations due to AEs. Conclusions: The PK of both glyburide and mefformin in the 10-12 year old age group was similar to that in the 13-16 year old age group. A single oral 1.25 mg/250 mg G/M tablet was safe and well-tolerated in these pediatric subjects.
PIII-15 LONG-TERM PHARMACOTHERAPY FOR WEIGHT LOSS
IN PATIENTS WITH OBESITY. R. S. Padwal, MD, S. K. Li, MD, D. Lau, MD, University of Toronto, Sunnybrook and Women's College Hospital, University of Calgary, Toronto, Canada.
Purpose: To systematically review the effectiveness and safety of approved anti-obesity medications for promoting weight loss in dou- ble blind, placebo-controlled randomized trials with follow-up peri- ods of one year or greater.
Methods: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and Current Science Meta-register of Controlled Trials were searched. To identify unpublished studies, obesity experts and phar- maceutical companies were contacted. Abstracts and pseudo- randomized trials were not included. No language restriction was imposed. Results: Eight orlistat (n=4396) and 3 sibutramine (n=929) studies met the inclusion criteria. All patients received lifestyle modification. Attrition rates averaged 33% in the orlistat studies and 48% in the sibutramine studies. Compared to placebo, orlistat-treated patients displayed a 2.8% (95% CI: 2.2% to 3.5%) greater reduction in percentage of baseline body weight and patients on sibutramine, a 4-5.5% greater weight loss (p<0.05 for all three studies) after one year of follow-up. The number of patients achieving 10% or greater weight loss was 13% (95% CI: 9% to 17%) higher with orlistat and 15% (95% CI: 4% to 27%) higher with sibntramine compared to placebo. Orlistat caused increased GI side effects and sibutramine was associated with small increases in blood pressure.
Conclusion: Orlistat and sibutramine are modestly effective in promoting weight loss, although a subset of patients may achieve greater benefit.
PIII-16 LACK OF EFFECT OF APREPITANT ON DIGOXIN PHAR
MACOKINETICS 1N HEALTHY SUBJECTS. Y. Lee, PhD, L. H. Oflowski, MS, N. Michiels, K. J. Petty, MD, PhD, M. R. Goldberg, MD, PhD, J. Dru, C. M. Chavez-Eng, M. Constanzer, G. Murphy, MD, K. Gottesdiener, MD, M. Hesney, MS, M. Feuring, M. Wehling, Merck & Co., Inc., lnstitut fur Klinische Phannakologie, West Point, PA.
Aprepitant is a highly selective antagonist of the neurokinin-1 (NK-1) receptor that, in combination with a corticosteroid and a 5-hydroxytryptamine 3 (5HT3) receptor antagonist, has been shown to be highly effective in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting (CINV). Since in clini- cal practice aprepitant might be coadministered with digoxin (a p-glycoprotein substrate) or other p-glycoprotein substrates, this study investigated whether aprepitant affects the plasma concentra- tions and urinary excretion of immunoreactive digoxin in healthy subjects. In a double-blind, placebo-controlled, randomized, two- period, crossover study, 12 subjects were dosed for 13 days in 2 separate periods. During both treatment periods (A and B), subjects received daily oral doses of digoxin 0,25 mg on Days 1 through 13. In Treatment A, subjects received a single oral dose of aprepitant 125 mg on Day 7 and single oral doses of aprepitant 80 rag/day on Days 8 through 11. In Treatment B, subjects received aprepitant placebo with digoxin. The geometric mean ratios (90% CI) for plasma AUCo-24 hr of immunoreactive digoxin (with/without aprepitant) were 0.99 (0,91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively. The geometric mean ratios (90% CI) for 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. In conclusion, the aprepitant dosing regimen for the prevention of CINV did not affect the pharmacokinefics of digoxin. This suggests that the aprepitant regimen for CINV is unlikely to produce clinically significant pharmacokinetic interactions with drugs that are substrates of the p-glycoprotein transporter.
PIII-17 POPULATION PHARMACOKINETIC (PPK) MODELING
AND SIMULATION-DERIVED DOSING OF INTRAVENOUS BUSULFAN (BUSULFEX) IN PEDIATRIC PATIENTS. B . P . Booth, PhD, A. Rahman, PhD, R. N. Dagher, MD, D. Griebel, MD, A. Lai, PhD, S. Lennon, D. Fuller, MD, J. V. Gobburu, PhD, FDA\CDER\OCPB, FDA\CDER\OND, CPKD Solutions, Orphan Medical, Inc., Rockville, MD.
Purpose: There are varying approaches to dosing busulthn (Bu) in pediatric patients. The objective was to characterize the PK of Busulfex (IVBU) and provide pediatric dosing recommendations to consistently achieve appropriate systemic exposure (SE).
Methods: Twenty-four pediatric patients (0.5 to t7y) were treated with IVBU Q.I.D. for 4 days. Starting doses were 1.0 or 0.8mg/kg for ages -<4y or >4y, respectively. Target SE was 900 - 1350 ~M.min. About 20 plasma samples per patient were collected over 4 days. PPK models were developed using NONMEM. Body weight (BW), age, gender, and body surface area (BSA) were explored for covariate effects and Monte Carlo simulations performed.
Results: The PK of IVBU were described by a one-compartment model with clearance (CL) 3.37 ml/min/kg and volume of distribu- tion (V) of 0.64 L/kg. The terminal tl/2 was 2h. Simulations using various mg/m 2 and mg/kg regimens indicated the best mg/kg regimen (using 2 dose levels) was similar to the best mg/m 2 regimen, and achieved the desired first dose SE in approximately 60% of pediatric patients.
Conclusions: The PPK model adequately characterized the behav- ior of IVBU in pediatric patients. BW dosing was selected for clinical utility. This model suggests that patients ~< 12 kg should be dosed at 1.1 mg/kg, and those >12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment based on dose 1 may further improve therapeutic targeting.
