The Pharmacokinetics of Extended‐Release Formulations of Calcium Antagonists and of Amlodipine in Subjects with Different Gastrointestinal Transit Times

Abstract

The influence of gastrointestinal (GI) transit times on the pharmacokinetics (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 extended-release formulation of 10 mg felodipine (FEL), and 5 mg amlodipine (AML) 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 parameters in the rapid versus slow transit group were the following: trough levels (C24 h): 22.8 +/- 8.3 versus 49.5 +/- 35.7 ng/ml, p < 0.05; AUC 1134.4 +/- 512.7 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 times, nor was Cmax after any of the three treatments. Variations in PK parameters, as indicated by coefficients of variation, were about twofold higher for both DIL and FEL, compared to AML. Variations in mean residence times were 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 (Cmax/C24 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 intrinsically slow elimination such as amlodipine. The pharmacokinetics of the CCBs with formulation-based once-a-day characteristics are sensitive to GI transit if these processes are rapid enough to interfere with the formulation-specific release profile.

Confounding factors for sex differences in pharmacokinetics and pharmacodynamics: Focus on dosing regimen, dosage form, and formulation

“…The longer GI residence time for sustained‐release dosage forms may further facilitate more drugs to be absorbed in the gut for women. This seems to be consistent with the observation that the PK of a diltiazem extended‐release formulation administered once a day is sensitive to the GI transit time 72 …”

“…This seems to be consistent with the observation that the PK of a diltiazem extended-release formulation administered once a day is sensitive to the GI transit time. 72 With the advances in pharmaceutic science and technology, it is noteworthy that each modified-release dosage form may possess its own unique release mechanism and release profile of the drug. For example, the GI therapeutic system (GITS) for Procardia XL (Pfizer, New York, NY), nifedipine extended-release tablets, is fabricated to provide a drug delivery rate independent of pH or motility of the GI tract.…”

Chiral Cardiovascular Drugs

“…69,70 In a three-way crossover design, the single-dose pharmacokinetics of a controlled-delivery formulation of 240 mg of diltiazem, an extended-release formulation of 10 mg of felodipine, and 5 mg of amlodipine were compared in two groups of healthy subjects with either slow (0.35 hour) or rapid (,15 hours) gastrointestinal transit as assessed by the metal detector method (EAS II). Gastrointestinal transit significantly affected the pharmacokinetics of diltiazem.…”

Diagnostic uses of metal detectors: a review

“…Introduced in 1989 (42), the metal detector method for measuring GI transit times has been used to study variations in gastric emptying time with various foods (43), the influence of various laxatives on colonic transit time (44,45), how erythromycin affects GI transit time (46), the effects of diabetes on GI transit times (47,48) and the effects of prokinetic drugs in patients with progressive systemic scleroderma (49). The metal detector method has also been used to divide research subjects into slow or rapid GI transit groups for drug studies (50). Metal detectors have also been used to track a diagnostic monitoring device such as a pH metre during its transit of the GI tract (51).…”