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 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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
1999 |
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| Erschienen: |
1999 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:39 |
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| Enthalten in: |
Journal of clinical pharmacology - 39(1999), 10 vom: 01. Okt., Seite 1021-31 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zimmermann, T [VerfasserIn] |
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| Themen: |
1J444QC288 |
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| Anmerkungen: |
Date Completed 27.10.1999 Date Revised 26.08.2019 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM104476834 |
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| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
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| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zimmermann, T |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The pharmacokinetics of extended-release formulations of calcium antagonists and of amlodipine in subjects with different gastrointestinal transit times |
| 264 | 1 | |c 1999 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 27.10.1999 | ||
| 500 | |a Date Revised 26.08.2019 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial | |
| 650 | 4 | |a Comparative Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 7 | |a Calcium Channel Blockers |2 NLM | |
| 650 | 7 | |a Delayed-Action Preparations |2 NLM | |
| 650 | 7 | |a Amlodipine |2 NLM | |
| 650 | 7 | |a 1J444QC288 |2 NLM | |
| 650 | 7 | |a Diltiazem |2 NLM | |
| 650 | 7 | |a EE92BBP03H |2 NLM | |
| 650 | 7 | |a Felodipine |2 NLM | |
| 650 | 7 | |a OL961R6O2C |2 NLM | |
| 700 | 1 | |a Laufen, H |e verfasserin |4 aut | |
| 700 | 1 | |a Yeates, R |e verfasserin |4 aut | |
| 700 | 1 | |a Scharpf, F |e verfasserin |4 aut | |
| 700 | 1 | |a Riedel, K D |e verfasserin |4 aut | |
| 700 | 1 | |a Schumacher, T |e verfasserin |4 aut | |
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| 952 | |d 39 |j 1999 |e 10 |b 01 |c 10 |h 1021-31 | ||