The pharmacokinetics of extended-release formulations of calcium antagonists and of amlodipine in subjects with different gastrointestinal transit times

The influence of gastrointestinal (GI) transit times on the pharmacokinetic s (PK) of three calcium channel blockers (CCBs), recommended for once-daily dosing, was investigated. In a three-way crossover design, the single-dose PK of a controlled-delivery formulation of 240 mg diltiazem (DIL), an exte nded-release formulation of 10 mg felodipine (FEL), and 5 mg amlodipine (AM L) were compared in two groups of healthy subjects, with either slow (> 35 h) or rapid (< 15 h) GI transit, as assessed by the metal detector method ( EAS II). GI transit significantly affected the PK of DIL. Mean PK parameter s in the rapid versus slow transit group were the following: trough levels (C-24h: 22.8 +/- 8.3 versus 49.5 +/- 35.7 ng/ml, p < 0.05; AUC 1134.4 +/- 5 12.7 versus 1704.7 +/- 1185.6 hng/ml, p < 0.05 (one-sided). Neither AUC nor trough levels of FEL and AML were significantly influenced by transit time s, nor was C-max after any of the three treatments. Variations in PK parame ters, as indicated by coefficients of variation, were about twofold higher for both DIL and FEL, compared to AML. Variations in mean residence times w ere significantly lower for AML compared to DIL and FEL (7% vs. 30% and 17% , p < 0.001 and p < 0.002, respectively). Peak-to-trough ratios (C-max/C-24 h mean) were 1.8 +/- 0.9 for DIL, 7.6 +/- 3.5 for FEL, and 1.7 +/- 0.2 for AML. In conclusion, the predictability of pharmacokinetic behavior both in conditions of rapid or slow GI transit is optimized in drugs with intrinsic ally slow elimination such as amlodipine. The pharmacokinetics of the CCBs with formulation-based once-a-day characteristics are sensitive to GI trans it if these processes are rapid enough to interfere with the formulation-sp ecific release profile. Journal of Clinical Pharmacology 1999;39:1021-1031 (C)1999 the American College of Clinical Pharmacology.