Comparative bioavailability of two formulations containing atenolol and chlortalidone associated in a 4 : 1 fixed combination

Atenolol (CAS 29122-68-7) and chlortalidone (CAS 77-36-1) are marketed asso ciated in a 4:1 strength ratio (100/25 and 50/12.5 mg) for the treatment of hypertension. According to EU guidelines, the bioequivalence of one dosage strength call also cover additional strengths when the pharmacokinetics of a given drug is linearly related with the dose. The kinetics of atenolol i s linearly correlated with the dose and chlortalidone has linear kinetics w ith doses less than or equal to 100 mg. Thus this trial carried out on the 100/25 mg strength also covers the 50/12.5 mg strength. The trial was carried out on 18 healthy volunteers (9 males and 9 females) according to a single dose, two-period, two-treatment, two-sequence study d esign with washout. Timed atenolol plasma concentrations and chlortalidone blood concentrations were used to assess primary pharmacokinetic parameters C-max, t(max) and AUC extrapolated to infinity by a non-compartmental mode l. The bioavailability of the two formulations was compared through the 90% confidence intervals (C.I.) of C-max and AUC in accordance with operating guidelines. C.I. of chlortalidone were fully comprised in the 0.80-1.25 ran ge. In the case of atenolol, which displayed a higher data dispersion, C.I. were comprised in the enlarged 0.70-1.43 range. Time to peak, t(max), did not show any statistically significant difference between the test and refe rence product with respect to both analytes. Pharmacodynamic measurements o f the decrease in systolic blood pressure led to fully overlapping results with test and reference. The authors conclude that the test formulation should be considered bioequi valent with the reference with chlortalidone and in the borderline of bioeq uivalence with atenolol. As no safety problems were involved and pharmacody namics led to overlapping results as between test and reference, the bioequ ivalence conclusion could be extended also to atenolol.