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Population pharmacokinetics of cyclosporine : influence of covariables and assessment of cyclosporine absorption in kidney, lung, heart and heart + lung transplanted patients
Population Pharmacokinetics of Cyclosporine: Influence of Covariables and Assessment of Cyclosporine Absorption in Kidney, Lung, Heart and Heart 1 Lung Transplanted Patients L-E.B. Kyhl, S.N. Rasmussen, L. Aarons, and S.B. Jensen
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N A MULTI-CENTER study the population pharmacokinetics of cyclosporine were examined. Seven hundred twenty-eight kidney transplanted outpatients in seven centers and 151 heart/lung/heart 1 lung transplanted outpatients in four centers received cyclosporine (Neoral capsules, Novartis Pharma Inc, Basel, Switzerland) orally twice a day. No restrictions were introduced to habits. Two thousand nine hundred ninety-eight cyclosporine/blood component concentrations were obtained in the kidney transplanted group and 619 cyclosporine/blood component (creatinine, uricacid, alat, alkaline phosphatase, total bilirubin, urea albumin, sodium, potassium, haemoglobin, haematocrit, leucocytes, thrombocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils) concentrations in the heart/lung/heart 1 lung transplanted group. The average dose administrated before each concentration measurement was 143.9 mg (range 25.0 to 500.0 mg) in the kidney transplanted group and 187.7 mg (range 50 to 400 mg) in the heart/lung/heart 1 lung transplanted group. The average number of measurements per patient was 4.1 in both groups (range 1 to 5). Eight hundred thirty cyclosporine concentrations in the kidney transplanted group were obtained 0 to 4 hours after cyclosporine dosing, 238 4 to 8 hours after dosing, 811 8 to 12 hours after dosing, 957 12 to 16 hours after dosing, and 162 at more than 16 hours after dosing. In the heart/lung/heart 1 lung group the figures were 119, 28, 316, 152, and 4, respectively. The pharmacokinetics calculations were carried out with NONMEM.1 A two-compartment open model with zero order absorption were used. Different covariables (blood components, sex, dose, age, race, weight, height, diagnosis, days since transplantation, systolic/diastolic blood pressure,
0041-1345/98/$19.00 PII S0041-1345(98)00390-X 1680
pulse and groups of other drugs) were incorporated into the model but no covariables seemed to influence the calculated cyclosporine concentration. On a plot of the predicted versus the observed cyclosporine concentration it can be seen that a group of patients have an observed cyclosporine concentration below 0.25 mg/mL and a predicted cyclosporine concentration between 0.25 and 1.6 mg/mL. It was found that these concentrations were obtained 0 to 3 hours after cyclosporine dosing and that the demographics for these patients are similar to the rest of the patients. A plot of the observed concentration versus time after dosing shows that the patients with an observed cyclosporine concentration under 0.25 mg/mL and a predicted cyclosporine concentration between 0.25 and 1.6 mg/mL tend to have a lower maximum concentration. The conclusion of the study is that no covariables seem to influence the calculated cyclosporine concentration, and some patients show an absorption pattern different from the majority of patients. REFERENCES 1. Boeckmann AJ, Sheiner LB, Beal SL: NONMEM Users Guide, San Francisco: NONMEM Project Group; 1989
From The Royal Danish School of Pharmacy, Department of Pharmacology, Copenhagen, Denmark; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK; and Novartis Healthcare A/S, Pharma, Copenhagen, Denmark. This study is sponsored by Novartis Pharma AG. Address reprint requests to Dr Lars-Erik Kyhl, The Royal Danish School of Pharmacy, Department of Pharmacology, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 1680 (1998)
I
N A MULTI-CENTER study the population pharmacokinetics of cyclosporine were examined. Seven hundred twenty-eight kidney transplanted outpatients in seven centers and 151 heart/lung/heart 1 lung transplanted outpatients in four centers received cyclosporine (Neoral capsules, Novartis Pharma Inc, Basel, Switzerland) orally twice a day. No restrictions were introduced to habits. Two thousand nine hundred ninety-eight cyclosporine/blood component concentrations were obtained in the kidney transplanted group and 619 cyclosporine/blood component (creatinine, uricacid, alat, alkaline phosphatase, total bilirubin, urea albumin, sodium, potassium, haemoglobin, haematocrit, leucocytes, thrombocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils) concentrations in the heart/lung/heart 1 lung transplanted group. The average dose administrated before each concentration measurement was 143.9 mg (range 25.0 to 500.0 mg) in the kidney transplanted group and 187.7 mg (range 50 to 400 mg) in the heart/lung/heart 1 lung transplanted group. The average number of measurements per patient was 4.1 in both groups (range 1 to 5). Eight hundred thirty cyclosporine concentrations in the kidney transplanted group were obtained 0 to 4 hours after cyclosporine dosing, 238 4 to 8 hours after dosing, 811 8 to 12 hours after dosing, 957 12 to 16 hours after dosing, and 162 at more than 16 hours after dosing. In the heart/lung/heart 1 lung group the figures were 119, 28, 316, 152, and 4, respectively. The pharmacokinetics calculations were carried out with NONMEM.1 A two-compartment open model with zero order absorption were used. Different covariables (blood components, sex, dose, age, race, weight, height, diagnosis, days since transplantation, systolic/diastolic blood pressure,
0041-1345/98/$19.00 PII S0041-1345(98)00390-X 1680
pulse and groups of other drugs) were incorporated into the model but no covariables seemed to influence the calculated cyclosporine concentration. On a plot of the predicted versus the observed cyclosporine concentration it can be seen that a group of patients have an observed cyclosporine concentration below 0.25 mg/mL and a predicted cyclosporine concentration between 0.25 and 1.6 mg/mL. It was found that these concentrations were obtained 0 to 3 hours after cyclosporine dosing and that the demographics for these patients are similar to the rest of the patients. A plot of the observed concentration versus time after dosing shows that the patients with an observed cyclosporine concentration under 0.25 mg/mL and a predicted cyclosporine concentration between 0.25 and 1.6 mg/mL tend to have a lower maximum concentration. The conclusion of the study is that no covariables seem to influence the calculated cyclosporine concentration, and some patients show an absorption pattern different from the majority of patients. REFERENCES 1. Boeckmann AJ, Sheiner LB, Beal SL: NONMEM Users Guide, San Francisco: NONMEM Project Group; 1989
From The Royal Danish School of Pharmacy, Department of Pharmacology, Copenhagen, Denmark; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK; and Novartis Healthcare A/S, Pharma, Copenhagen, Denmark. This study is sponsored by Novartis Pharma AG. Address reprint requests to Dr Lars-Erik Kyhl, The Royal Danish School of Pharmacy, Department of Pharmacology, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 1680 (1998)