Steady-State Pharmacokinetics of High-Dose Diltiazem Hydrochloride (Cardizem CD) Administered Once Daily in Healthy Volunteers

Robbins-Weilert, Doris K.; Giesing, Dennis H.; Weir, Scott J.

doi:10.1097/00045391-199907000-00006

Cited by 5 publications

(6 citation statements)

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“…Plasma concentration‐time profiles for CR and XR diltiazem were simulated using Simcyp. The pharmacokinetic parameters are shown in Table III and are compared with observed data previously reported in the literature 3 , 8 Figure 2. shows the plasma concentration‐time profiles of diltiazem following administration of diltiazem XR once daily for 5 days.…”

Section: Resultsmentioning

confidence: 87%

“…(a) Simulated and observed steady‐state plasma concentration time‐profiles of diltiazem. The symbols are the mean diltiazem concentrations measured in clinical studies 8 ; the line represents the simulated mean concentration‐time profile of diltiazem using Simcyp. (b) Simulated active CYP3A content in the liver and the intestine over time following administration of 240 mg diltiazem XR once daily for 5 days.…”

Section: Resultsmentioning

confidence: 99%

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Effect of Different Durations and Formulations of Diltiazem on the Single-Dose Pharmacokinetics of Midazolam: How Long Do We Go?

Friedman

Fraser

Wang

et al. 2011

The Journal of Clinical Pharmacology

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Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compound's sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single-dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazem(XR × 5 days)/midazolam + diltiazem(XR × 2 days)) for midazolam AUC(0-∞) was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazem(XR × 2 days)/midazolam + diltiazem(CR × 2 days)) for midazolam AUC(0-∞) was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (k(deg)) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h(-1) should be considered for future Simcyp studies.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Effect of Different Durations and Formulations of Diltiazem on the Single-Dose Pharmacokinetics of Midazolam: How Long Do We Go?

Friedman

Fraser

Wang

et al. 2011

The Journal of Clinical Pharmacology

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“…For each divided minidose, the simulation was run using the first-order absorption model and onecompartment distribution model. In addition, for the diltiazem SR formulation, the values of systemic clearance and volume of distribution of diltiazem were changed to 48.3 l/h with a coefficient of variation (CV) value of 27% and 5.2 l/kg with a CV value of 27.2%, respectively (Ochs and Knü chel, 1984) to simulate the observed diltiazem plasma profile (Robbins-Weilert et al, 1999). In vitro mechanism-based inactivation parameters were added to the interaction profiles of saquinavir, ritonavir, and fluoxetine (Table 3) when simulations were performed using 0.03 h Ϫ1 as the k deg value for hepatic CYP3As.…”

Section: Methodsmentioning

confidence: 99%

Confidence Assessment of the Simcyp Time-Based Approach and a Static Mathematical Model in Predicting Clinical Drug-Drug Interactions for Mechanism-Based CYP3A Inhibitors

Wang¹

2010

Drug Metab Dispos

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ABSTRACT:Accurate prediction of the extent of mechanism-based CYP3A inhibition is critical in determining the timing of clinical drug interaction studies in drug development. To evaluate the prediction accuracy of the static and Simcyp time-based approaches, 54 clinical drug interactions involving mechanism-based CYP3A inhibitors were predicted using both methods. The Simcyp timebased approach generated better prediction when 0.03 h ؊1 was used as the hepatic CYP3A enzyme degradation rate constant (k deg ) value. Of the predictions 87 and 55% had an error less than 2 and 0. Drug-drug interactions remain an area of focus in drug discovery and development. Mechanism-based inhibition of CYP3A is one of the major causes of clinical drug-drug interactions and generally leads to greater concern, as highlighted by the list of moderate and strong CYP3A inhibitors in the Food and Drug Administration (2006) Drug Interaction Guidance. The inhibitory effects of a mechanism-based CYP3A inhibitor persist long after the compound is eliminated from the body because the recovery of CYP3A enzyme activity requires de novo protein synthesis or slow release of the enzyme from the enzyme-inhibitor complex. Because of the primary role of CYP3A in drug disposition, prediction of the clinical drug interaction potential of a mechanism-based CYP3A inhibitor would be helpful in guiding the timing and design of clinical studies.Several approaches have been developed to predict clinical outcomes of mechanism-based inhibition. The static mathematical model developed by Mayhew et al. (2000) is a commonly used approach to predict mechanism-based drug interactions from in vitro estimated inactivation parameters. Several modifications to the original model have been made to incorporate the effects of intestinal wall metabolism (Wang et al., 2004b), competitive inhibition, and induction (Fahmi et al., 2009). Nonetheless, these static models are only capable of predicting the average magnitude of drug interactions across a population, assuming that the steady state of enzyme inhibition has been reached. Temporal changes in inhibitor concentrations and CYP3A enzyme activities as well as interindividual variability in CYP3A enzyme levels and rate constants of enzyme degradation are not considered. In addition, it is difficult to assess the effects of dosing regimens (e.g., irregular dosing) on the extent of drug interactions using a static model.Several physiologically based pharmacokinetic models (PBPK) were developed to address some of the aforementioned limitations with static models (Kanamitsu et al., 2000;Zhang et al., 2009;Fenneteau et al., 2010). These PBPK models take into account temporal changes in inhibitor and substrate concentrations and enzyme activities as well as the enzyme inhibition concept in the static models. They can be used to simulate drug concentrationtime profiles and to explore the effects of various dosing regimens. Simcyp (Simcyp Limited, Sheffield, UK) is a commercially available absorption, distribution, metabolism, and...

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“…These days diltiazem is readily measured in blood and so there are a number of published studies reporting on the concentration-response relationship for diltiazem [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. However, the literature on diltiazem is full of conflicting evidence because the limited original data correlating serum concentration with therapeutic effect have proved difficult to interpret.…”

Section: Minimum Effective Concentration and Minimum Effective Dosementioning

confidence: 99%

“…In bioavailability studies in healthy volunteers, Robbins-Weilert et al [14] quote a minimum concentration of 40 ng/ml [17] 11 120 d Single oral -4100 Reduction in SVR Morselli et al [19] 60 120-180 d Single oral Angina NR *45 R *78 Opie [11] 50-300 In vitro extrapolation Posma et al [8] 12 120 bd 21 days oral Angina 79 13% increase in ETT Chaitman et al [12] 9 120 d Single oral Angina 4150 Increase in ETT42 min Dias et al [ for symptomatic improvement in patients with hypertension or angina and cite a review by Buckley et al [15] in support. The same minimum value is quoted by Bianchetti et al [16] referring to an abstract by Taeymans et al [17] as evidence.…”

Section: Minimum Effective Concentration and Minimum Effective Dosementioning

confidence: 99%

Untitled

Mould

2002

Int J Pharm Med

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Diltiazem is a calcium antagonist effective in the treatment of stable and unstable angina and mild to moderate systemic hypertension with a generally favourable side-effect profile. A number of published studies have attempted to formulate a therapeutic target range, but there appears to be little consensus of opinion. A minimum effective concentration of 40 ng/ ml has been proposed by some authors whilst others have chosen 50 ng/ml and others upwards to 100 ng/ml. A review of the reports suggests that a trough concentration of above 50 ng/ml confers a better therapeutic outcome than does the lower concentrations. A number of modified release preparations enabling once a day dosing are available, all purporting to give adequate therapeutic concentrations. However, based on the above assumptions it would appear that those giving sustained concentrations above 50 ng/ml would be those of choice. Furthermore the benefits of once daily preparations lead to improved compliance and therefore improved therapeutic outcome and thus confirm that the modified preparations are the delivery of choice. Once chosen, it is advisable to maintain the same preparation in order to derive maximum clinical benefit.

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Steady-State Pharmacokinetics of High-Dose Diltiazem Hydrochloride (Cardizem CD) Administered Once Daily in Healthy Volunteers

Cited by 5 publications

References 0 publications

Effect of Different Durations and Formulations of Diltiazem on the Single-Dose Pharmacokinetics of Midazolam: How Long Do We Go?

Effect of Different Durations and Formulations of Diltiazem on the Single-Dose Pharmacokinetics of Midazolam: How Long Do We Go?

Confidence Assessment of the Simcyp Time-Based Approach and a Static Mathematical Model in Predicting Clinical Drug-Drug Interactions for Mechanism-Based CYP3A Inhibitors

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