Reduced Inter- And Intrasubject Variability in Cyclosporine Pharmacokinetics in Renal Transplant Recipients Treated With a Microemulsion Formulation in Conjunction With Fasting, Low-Fat Meals, or High-Fat Meals1,2

Bd, Kahan; Dunn, John Shaw; Fitts, Charles T.; D, Van Buren; Wombolt, Duane G.; Pollak, Raymond; Carson, Richard W.; Jw, Alexander; Choc, Milan; Wong, Robert

doi:10.1097/00007890-199502270-00011

Cited by 93 publications

(70 citation statements)

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“…DWC.AUC[0-4] and DWC.AUC [0][1][2][3][4][5][6][7][8][9][10][11][12] approximately doubled in value during the first 3 months post-transplant, but whether this change was continuous throughout this period or reached a threshold value at a specific time is impossible to determine in view of the absence of measures between day 14 and day 84. However, data from a prior international multicenter study in de novo renal transplantation during which kinetics were evaluated from 2 weeks to 3 months post-transplant suggests that absorption may stabilize between 1 and 2 months after commencing therapy (31).…”

Section: Discussionmentioning

confidence: 99%

“…The 4-point predictor C0 π C1 π C2 π C3 performed well (mean R 2 Ω 0.84), but was not superior to several 2-and 3-point predictors. Subsequent analysis including all time-points throughout the dosing interval showed that later time points were more important in predicting AUC [0][1][2][3][4][5][6][7][8][9][10][11][12]. While C3 remained the best single-point predictor (mean R 2 Ω 0.72), C1.5 π C6 provided the best 2-point performance (mean R 2 Ω 0.88), and multipoint predictors including sample times at Cmax (C1-C2.5) and at intervals throughout the elimination phase (C3-C12) offered the best overall correlation (not shown).…”

Section: Prediction Of Absorption Profilementioning

confidence: 99%

“…The microemulsion formulation of CsA (Neoral TM , Novartis Pharma, Basle, Switzerland), which provides enhanced absorption with relative independence from the effects of food, bile flow and gastrointestinal dysfunction, resulting in lower inter-and intraindividual variability of exposure, offers an important opportunity to optimize this approach (7)(8)(9)(10)(11). CsA concentration monitoring is normally performed using a single pre-dose specimen to measure whole blood 'trough' concentration (C0).…”

Section: Introductionmentioning

confidence: 99%

“…However, this measure does not accurately predict drug exposure, estimated by the area under the time-concentration curve (AUC) (4,6). Since it is generally impractical to perform extensive pharmacokinetic (PK) studies on patients under conditions of normal practice, pharmacokinetic modeling has been used to develop a simple and alternative sparse-sampling method for AUC over the entire 12-h dosage interval (AUC [0][1][2][3][4][5][6][7][8][9][10][11][12]) monitoring in clinical practice (12,13). Studies have suggested a variety of models using time-points throughout the dosing interval for use in clinical practice (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…We describe here the significant change in absorption profile and relative absorption which occurs during the first 3 months after renal transplantation; we identify the simplest and most practical sparse-sampling methods for prediction of absorption profile during this time, and demonstrate that the choice of predictors differs importantly when measuring AUC [0][1][2][3][4] or AUC [0][1][2][3][4][5][6][7][8][9][10][11][12]. The feasibility, accuracy, precision and utility of absorption profiling are reported in the companion article.…”

Section: Introductionmentioning

confidence: 99%

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Cyclosporine Microemulsion (Neoral®) Absorption Profiling and Sparse-sample Predictors During the First 3 Months after Renal Transplantation

Keown

Cole

Muirhead

et al. 2002

American Journal of Transplantation

129

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Recent data suggest that optimal cyclosporine (CsA) exposure early post-transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration-controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral. An international, prospective, multicenter study examined the feasibility, accuracy, precision and clinical utility of cyclosporine microemulsion (Neoral A ) absorption profiling in de novo renal transplant recipients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression. The nested pharmacokinetic study reported here was conducted in 4 study centers in which full (11-point) pharmacokinetic profiles were performed on days 3, 7, 14 and 84 post-transplant to examine absorption profile and absorption efficiency, and to determine optimal sparse-sampling pharmacokinetic methods to predict Neoral exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Prediction Of Absorption Profilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cyclosporine Microemulsion (Neoral®) Absorption Profiling and Sparse-sample Predictors During the First 3 Months after Renal Transplantation

Keown

Cole

Muirhead

et al. 2002

American Journal of Transplantation

129

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Generic substitution for immunosuppressive drugs

Helderman

2011

Dialysis & Transplantation

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The advent of generic alternatives for transplant immunosuppressant drugs has engendered concern and discussion. The process by which the food and drug administration (FDA) approves generic substitutes is reviewed. A category of medicines deﬁned as narrow therapeutic index (NTI) drugs is deﬁned with evidence that many (but not all) of the commonly used transplant medications fall into this category. It is demonstrated that the current FDA standards are inadequate to vet NTI agents. Outcomes data are presented that show generic switching for NTI drugs can be successfully accomplished with careful blood level monitoring, but clinical and ﬁnancial negative consequences can ﬂow from unregulated switching. Recommendations are made for provider use of generic immunsuppressants, for recipient education and response to switching, and for pharmacy shandling of generic alternatives.

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Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults

Yang

Nikanjam

Capparelli

et al. 2019

The Journal of Clinical Pharma

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We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2‐compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single– or 2–time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration–time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single– and 2–time point limited sampling models estimated area under the plasma concentration–time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4‐ and 6‐hour limited sampling model had acceptable limits of r2, bias, and precision. Consequently, development of a single– or 2–time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.

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Reduced Inter- And Intrasubject Variability in Cyclosporine Pharmacokinetics in Renal Transplant Recipients Treated With a Microemulsion Formulation in Conjunction With Fasting, Low-Fat Meals, or High-Fat Meals1,2

Cited by 93 publications

References 0 publications

Cyclosporine Microemulsion (Neoral®) Absorption Profiling and Sparse-sample Predictors During the First 3 Months after Renal Transplantation

Cyclosporine Microemulsion (Neoral®) Absorption Profiling and Sparse-sample Predictors During the First 3 Months after Renal Transplantation

Generic substitution for immunosuppressive drugs

Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults

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