Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients
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Ciclosporin
On the basis of reports that diltiazem may bind to the hepatic microsomal enzymes and inhibits the metabolism of some co-administered drugs, and to determine the effects of diltiazem on theophylline pharmacokinetics in patients with bronchospastic airway disease, we have investigated the effect of a 180-mg daily dose of oral diltiazem during 5 days on theophylline clearance in eight patients with that disease. Theophylline half-life increased 24%, from 5.7 +/- 1 to 7.5 +/- 1.8 h (p < 0.05), and total body theophylline clearance showed a decrease of 22%, from 87.3 +/- 20 to 68.3 +/- 18.6 ml/min (p < 0.05) after diltiazem therapy. The apparent volume of distribution was unchanged. This reduction in theophylline clearance is likely produced by inhibition of its metabolism by diltiazem. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently in patients with bronchospastic airway disease.
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A limited sampling model (LSM) was developed to estimate the area under the curve (AUC) and maximum plasma concentration (Cmax) for a 1-g oral dose of vigabatrin. The model was developed using the data from 10 healthy subjects and one time point. The following equations describe the model for AUC and Cmax: AUC(predicted) = 5.4 × C3h + 70 and Cmax(predicted) = 0. 18 × AUC(O-infinity) + 9.4. The model was validated in 49 subjects who orally received 1-g vigabatrin. This LSM was also used to predict AUC and Cmax volunteers who received 2- and 4-g vigabatrin doses and in renal failure patients who were given a 0.75-g dose. The model provided good estimates of both AUC and Cmax in all groups of subjects except renal dysfunction patients. The method described here may be used to estimate AUC and Cmax of vigabatrin without detailed pharmacokinetic studies.
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There is an ongoing debate on the use of a single concentration time point C2 for therapeutic drug monitoring (TDM) and exposure prediction for cyclosporine. The objective of the present work was to evaluate the relationship between the peak concentration (Cmax ) versus area under the curve (AUC) for cyclosporine. Using published data from renal transplant patients from an 8-12 week study with two formulations, a simple linear regression model represented by AUC - cyclosporine = Cmax - Cyclosporine × 3.9965 + 384.5 (r = 0.9647; p < 0.001) was developed. Using the regression equation, predictions of AUC from the reported Cmax data were performed; the fold difference between observed vs predicted AUC was computed and the root mean square error for the prediction was calculated. While all but one of the predicted AUCs were contained within a 0.5-2-fold difference (99.1%), a greater proportion of the AUC values were predicted within a narrower range of 0.75 to 1.5-fold difference (78.2%), suggesting the utility of Cmax as the right surrogate for predicting the AUC for cyclosporine with a correlation coefficient of 0.8698 (n = 126; p < 0.001) and a RMSE of 26.2%. Since the time to Cmax generally varies from 1 to 2 h, although the results validate the use of C2, there may be an opportunity to explore the suitability of C1 or C1.5 in a prospective study for the purpose of TDM and AUC prediction of cyclosporine.
Therapeutic Drug Monitoring
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OBJECTIVE—To assess the absorption profile of inhaled insulin in healthy, actively smoking subjects at baseline, after smoking cessation, and after smoking resumption and compare it with nonsmoking subjects. RESEARCH DESIGN AND METHODS—Insulin pharmacokinetics and glucodynamics were measured in 20 male smoking subjects (10–20 cigarettes/day) and 10 matched nonsmoking subjects after receiving inhaled insulin (1 mg) or the approximate subcutaneous insulin equivalent (3 units) in a randomized cross-over fashion. All smokers then received inhaled insulin 12 h, 3 days, and 7 days into a smoking cessation period. They then resumed smoking for 2–3 days before again receiving inhaled insulin 1 h after the last cigarette. RESULTS—Before smoking cessation, maximum insulin concentration (Cmax) and area under the curve (AUC) for insulin concentration time (AUC-Insulin0–360) with inhaled insulin were higher, and time to Cmax (tmax) shorter, in smokers than nonsmokers (Cmax 26.8 vs. 9.7 μU/ml; AUC-Insulin0–360 2,583 vs. 1,645 μU · ml−1 · min−1; tmax 20 vs. 53 min, respectively; all P < 0.05), whereas with subcutaneous insulin, systemic exposure was unchanged (AUC-Insulin0–360 2,324 vs. 2,269 μU · ml−1 · min−1; P = NS). After smoking cessation, AUC-Insulin0–360 decreased with inhaled insulin by up to 50% within 1 week and approached nonsmoker levels. Cmax decreased and tmax increased relative to baseline but were still not comparable with nonsmoker values. Smoking resumption completely reversed the effect of smoking cessation. Glucodynamics corroborated the observed findings in insulin pharmacokinetics. CONCLUSIONS—Cessation and resumption of smoking greatly altered the pharmacokinetics of inhaled insulin. As rapid changes in systemic insulin exposure increase hypoglycemia risk, inhaled insulin should not be used in people with diabetes who choose to continue smoking. This is consistent with recommendations that people with diabetes refrain from smoking altogether.
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Platelet aggregation with collagen, ADP and sodium arachidonate was significantly inhibited by 0.48 and 0.24 mg/ml of diltiazem but no significant effect occurred with 0.024 mg/ml of diltiazem. It is suggested that the antiplatelet property of diltiazem may be utilized in clinical setting and diltiazem may be tried synergistically with other antiplatelet drugs.
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Alterations in bioavailability of several drugs other than propranolol after the coadministration of diltiazem were investigated in dog and human. Diltiazem did not promote the bioavailability of dipyridamole and furosemide, but the plasma levels of diazepam and its metabolite, desmethyl-diazepam were remarkably increased by the coadministration of diltiazem in dog. On diltiazem-diazepam interaction in human, there was no significant observation. This species difference may be explained by the difference in metabolizing activity for diazepam in dog and human. Several other drugs were tested in dog and it was found that relationship between absolute availability of drugs and the promoting effect of diltiazem was significant. Namely, diltiazem enhanced the absorption of drugs with absolute availability less than 20%, indicating that underlying mechanisms were related to their first pass metabolism. It is considered that such a diltiazem interaction would be advantageous to reduce inter-individual variation in pharmacological effect and also to reduce doses of coadministrated drugs with high liver clearance.
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Diltiazem is a member of a class of pharmacologic agents that block the passage of calcium ions across cell membranes, the calcium‐channel blockers. Several investigators have reported a clinically important pharmacokinetic and pharmacologic interaction between digoxin and verapamil. 1–4 Despite earlier suggestions of such an interaction with nifedipine, recent works have convincingly shown that no pharmacokinetic changes occur. 5–7 Thus, it appears that nifedipine has no clinically significant interaction with digoxin. Similar work has been limited with diltiazem. A recent investigation by Yoshida and associates, 8 suggested no increase in digoxin serum concentration and a slight decrease in renal digoxin clearance after diltiazem had been added versus a control period. Rameis and co‐workers 9 recently reported a 22.4% increase in serum digoxin concentration when diltiazem was added. The purpose of this study was to further evaluate this potential interaction.
Pharmacokinetic interaction
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