Concentration-Controlled Trials

Johnston, Atholl; Holt, David W.

doi:10.2165/00003088-199528020-00001

Cited by 23 publications

(2 citation statements)

References 33 publications

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“…As the CCD procedure was unsuccessful in differentiating MPA exposure between the 2 arms, a conclusion regarding method effectiveness of CCD cannot be drawn. 56,109,110 This contrasts with the TCI trials, which clearly demonstrated that MPA exposure can be effectively controlled, leading to outcome benefits. 26,34,35…”

Section: Resultsmentioning

confidence: 87%

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention

et al. 2019

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Graft Loss and Mortality Outcomes from kidney transplantation remain suboptimal. 1-3 Effective immunosuppressive drugs, along with attention to cardiovascular disease 4 and prophylaxis against infection, 5 have significantly reduced rates of acute rejection (15.4%), graft loss (3.6%), and death (2.8%) in the first posttransplant year for standard risk recipients. 6 However, time to allograft failure remains substantially shorter than typical recipient life expectancy following transplantation, due largely to chronic antibody-mediated rejection. 7-10 Approximately 20% of kidney allograft

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Section: Resultsmentioning

confidence: 87%

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention

et al. 2019

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“…Concentration-controlled clinical trials have been proposed as a means to reduce pharmacokinetic variability and improve drug response rates (83). The complexity of implementation, the almost inevitable need for TDM-adjusted dosing in eventual clinical use, and the fact that pharmacokinetic variability is often not the major source for response variability have meant these trials have not been adopted into mainstream development (84)(85)(86). Effect or biomarker-controlled clinical trials represent an evolution of these study designs that can better explore sources of response variability, whether pharmacokinetic or pharmacodynamic (84,87).…”

Section: Trial Designs That Support Investigation Of Respondersmentioning

confidence: 99%

Precision Medicine Is Not Just Genomics: The Right Dose for Every Patient

Peck

2018

Annu. Rev. Pharmacol. Toxicol.

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Genomics has helped to initiate the era of precision medicine, with some drugs now prescribed on the basis of molecular genetic tests that indicate which patients are likely to respond or should not receive a drug because of a high risk of adverse effects. However, for precision medicine to realize its potential, the patient's history, environment, and lifestyle must also be taken into account. Improving precision medicine requires a better understanding of the underlying reasons for the variability in drug response so as to better identify which drug or combination of drugs is likely to be most effective for an individual patient, along with consideration of the optimal dose or doses for that patient. Greater individualization of dose will be an important means to achieve more precise medicine and mitigate significant variability in drug response. Achieving this will require changes in how drugs are developed, approved, prescribed, monitored, and paid for. Each of these factors is discussed in this review.

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Concentration‐Guided Strategies in Drug Development: Experience with a Cyclosporine Analog in Transplantation

Kovarik

Mueller

Kállay

et al. 1995

The Journal of Clinical Pharma

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A concentration-guided study was designed to maintain adequate immunosuppression and avoid excessive drug exposure while determining steady-state relative bioavailability of two cyclosporine G (CyG) oral formulations in stable renal transplant patients. In period I (week 1), 26 patients taking cyclosporine A (CyA)-based immunosuppressive regimens entered the study. Doses were titrated to maintain trough concentrations within a predefined range, as measured by fluorescence polarization immunoassay (FPIA). Patients were given an oral solution of CyG in period II (weeks 2-3), and a microemulsion capsule formulation of CyG in period III (weeks 4-5), with dose titration as necessary to achieve trough concentrations in a predefined range, as measured by FPIA. Full pharmacokinetic profiles were obtained on the last day of each study period. Treatment with CyA was reinitiated in period IV (week 6) at the same doses as at study entry. All blood samples were analyzed at the conclusion of the study using CyG- and CyA-specific high-performance liquid chromatography (HPLC). When changing from oral solution to capsule for CyG, an average 19% dose reduction was necessary to compensate for the elevated trough concentrations resulting from the increased bioavailability of the capsule formulation. The concentration-guided strategy was successful in avoiding over-exposure, and resulted in comparable values for area under the concentration-time curve (AUC) for both formulations of CyG. Dose normalization of the pharmacokinetic parameters subsequently allowed calculation of the relative bioavailability. Specifically, a faster rate and greater extent of CyG absorption from the capsule than the oral solution were manifested as a slightly earlier time to peak concentration (tmax), an average 44% increase in the maximum concentration (Cmax), and an average 29% increase in AUC. This experience demonstrated that a concentration-guided trial design allowed a drug development question for a compound with a narrow therapeutic index to be addressed safely and directly in the target patient population.

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Concentration-Controlled Trials

Cited by 23 publications

References 33 publications

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention

Precision Medicine Is Not Just Genomics: The Right Dose for Every Patient

Concentration‐Guided Strategies in Drug Development: Experience with a Cyclosporine Analog in Transplantation

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