PHARMACOKINETIC-PHARMACODYNAMIC MODELING AS A TOOL TO EVALUATE THE CLINICAL RELEVANCE OF A DRUG-FOOD INTERACTION FOR A NISOLDIPINE CONTROLLED-RELEASE DOSAGE FORM

Objective: Nisoldipine, a calcium antagonist of the dihydropyridine cl ass, has been used in the treatment of hypertension and angina pectori s. A new controlled-release dosage form (nisoldipine coat-core, NCC) h as been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for cont rolled-release dosage forms, a subsequent study was conducted to deter mine the clinical relevance of the changes in nisoldipine plasma conce ntration vs time profiles seen in the food effect study.Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started tr eatment with 20 mg NCC once daily (days 0-3, 5-6, 8-9). On days 4, 7 a nd 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution , respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant i ntake of food and NCC. Simultaneous measurements of blood pressure (BP ) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations a nd percentage reduction in BP [diastolic (DBP) and systolic (SBP), sup ine and standing] could be described by an E(max) model. The mean maxi mum reduction (E(max)) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standi ng), respectively. The interindividual variability (% CV) in E(max) wa s low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concen tration corresponding to 50% of the maximum effect (EC(50)) ranged bet ween 0.99 and 2.62 mu g . 1(-1) with a pronounced interindividual vari ability (% CV) of 89.5-108.8%. Mean C-max values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 mu g . 1(- 1), respectively. Based on the concentration-effect relationship estab lished in the present study, the effect achieved with a concentration of 7.5 mu g . 1(-1) will be about 77% of E(max) for DBP and about 88% of E(max) for SBP, respectively. Conclusion: At the time of maximum pl asma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. A fter administration of the 10 mg solution with a mean C-max of 8.7 mu g . 1(-1), only headache and flush with mild severity have been report ed as adverse events. These maximum concentrations are comparable to C -max values seen after intake of 40 mg NCC with food. With regard to h eart rate (HR) there were distinct differences between the two formula tions: Following administration of 5, 10 and 20 mg nisoldipine solutio n, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats . min(-1), respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.