Dinesh de Alwis(1), Leon Aarons(1) and Jonathan Palmer(2)
(1)Pharmacy Department, University of Manchester, Manchester Ml 7 9PL, UK; (2)Clinical Pharmacokinetics Department, GRD Ltd, Greenford UB6 OHE, UK
As part of a programme to model the variability of the pharmacokinetics of ondansetron we examined data arising from phase 1 studies in normal volunteers and in two patient groups: patients with renal impairment and patients with hepatic impairment.
In total three studies were used; Study 1 = 16 subjects, 8mg IV (15 minute infusion), Study 2 = 23 subjects, 8mg IV (15 minute infusion), Study 3 = 25 subjects, 8mg IV (5 minute infusion).
The number of post-dose samples used in analysis ranged from 14 to 20 per individual. The model which best described the data, based on individual nonlinear regression was a two-compartment model. This model was fitted to the data using NONMEM (version 1) assuming a multiplicative model to describe both the inter- and intra- individual subject variability.
It was found that the clearance of ondansetron was reduced in both renally impaired and hepatically impaired patients. Although the effect is not unknown (1), the influence of reduced renal function on ondansetron clearance would not have been readily predicted given that only 5% of unchanged drug is cleared renally in healthy subjects. Ondansetron clearance in males and females was found to be similar. A negative linear relationship was seen between ondansetron clearance and age.
The pharmacokinetic parameter estimates for the healthy volunteers (study 1) were as follows; CL = 32.4L/hr, V1 = 43.2L, VSS = 187.2L, CLD = 188L/hr.
The clearances from studies 2 and 3 are shown below:
| Group | Normals in | Renally impaired | Hepatically impaired | ||||
| CL(L/hr) | Renal Grp | HepaticGrp | Moderate | Severe | Mild | Moderate | Severe |
| 28.3 | 30.6 | 27.8 | 14.7 | 10.1 | 9.45 | 6.02 | |
It is planned to use this population model to explore data from the phase 2 and phase development programme.
Reference: PAGE 3 () Abstr 854 [www.page-meeting.org/?abstract=854]
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