Predicting Drug Candidate Victims of Drug-Drug Interactions, using Microdosing

Croft, Marie; Keely, Brendan J.; Morris, Ian D.; Tann, Lan; Lappin, Graham

doi:10.2165/11597070-000000000-00000

Cited by 37 publications

(54 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have recently shown that midazolam clearance in haematological patients taking posaconazole was inhibited to a similar extent compared with healthy volunteers using a 3 μg oral dose without any systemic benzodiazepine effects [12]. Even when combinations of strong inhibitors of midazolam such as ketoconazole/ fluoxetine were administered, which may increase exposure 12-fold [22], this phenotyping procedure is still safe, because even then effective concentrations will not be reached.…”

Section: Oral Application Intravenous Applicationmentioning

confidence: 99%

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Hohmann

Kocheise

Carls

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

AIMWe aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. METHODSIn an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics. RESULTS Dose CONCLUSIONThe pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Midazolam pharmacokinetics of oral doses are linear over a 30 000-fold range.• An oral microdose of midazolam is suitable to measure total CYP3A activity.• CYP3A inhibition with strong inhibitors can be evaluated with a microdose in healthy volunteers and patients. WHAT THIS STUDY ADDS• The pharmacokinetics of intravenous midazolam microdoses are linear to milligram doses.• The bioavailability and metabolic clearance of midazolam is similar after administration of microdoses and milligram doses.• Midazolam microdoses are a suitable tool to assess both systemic and pre-systemic CYP3A activity.

show abstract

Section: Oral Application Intravenous Applicationmentioning

confidence: 99%

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Hohmann

Kocheise

Carls

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Table 2 lists the compoundspecific preclinical input we used to predict the local C max values as input for the decision tree (Eqs. [1][2][3][4]. No P app was available for propafenone to estimate the fraction absorbed.…”

Section: Evaluation Of the Decision Tree With Selected Casesmentioning

confidence: 99%

“…Table 4 shows the C max values in intestinal lumen, enterocytes, liver, and plasma (total and unbound) as predicted from in vitro data and physicochemical properties (Eqs. [1][2][3][4][5][6][7][8]. The predicted C max in plasma is plotted against the observed C max for the therapeutic dose in the studies under consideration in Fig.…”

Section: Evaluation Of the Decision Tree With Selected Casesmentioning

confidence: 99%

“…In microtracer studies, a low dose of radiolabeled compound is added to a high dose of the unlabeled compound or a potentially interacting drug, by the same or alternate routes of administration. This allows gaining additional pharmacokinetic information cost effectively from already planned clinical trials, such as absolute oral bioavailability [1][2][3] and drug-drug interactions (DDIs) [4]. These (micro)tracer studies have become increasingly common in clinical drug development [12].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

Bosgra¹,

Vlaming²,

Vaes³

2015

Clin Pharmacokinet

View full text Add to dashboard Cite

Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates.

show abstract

“…It helps to obtain necessary pharmacokinetic data with a low dose of the candidate drug but without toxicity. Incorporating an intravenous micro dosing study into pharmacokinetic simulations we get reliable values with good predictability since intravenous data is a fundamental pharmacokinetic parameter to assess clearance and volume of distribution 21 . It also helps obtain preliminary data on the metabolism of a drug candidate.…”

Section: Applications Of Micro Dosingmentioning

confidence: 99%

Human Micro Dosing Studies (Phase 0): A Novel Approach in Clinical Research

Aiswarya¹,

Manohar²

2014

J Pharm Sci Innov.

View full text Add to dashboard Cite

Micro dosing or Phase 0 clinical trial is a breakthrough in drug development, where sub therapeutic dosages of various investigational products are administered under necessary safety conditions to minimal number of volunteers in order to obtain an early pharmacokinetic profile of the product. This important important bioanlaytic tool benefits patients as well as the pharmaceutical industry by bringing out new effective molecules faster and reducing the attrition rates at later clinical trial phases. This review encompasses the concept of micro dosing from its inception to its practical approaches till date in clinical research. The concept has evolved over the last decade from merely pharmacokinetic assessments to wider perspectives like drug-drug, drug-food interactions, bioavailability, oncology, metabolic profiling and use in vulnerable populations etc. which are discussed in this article. In future, micro dosing might emerge to be the standard predictive tool for human pharmacokinetics over alternative method and may continue to provide benefits that aren't fully realized up to date.

show abstract

Predicting Drug Candidate Victims of Drug-Drug Interactions, using Microdosing

Abstract: The initial data reported here demonstrate the utility of microdosing to investigate the risk of development drugs being victims of drug-drug interactions.

Cited by 37 publications

References 28 publications

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

Human Micro Dosing Studies (Phase 0): A Novel Approach in Clinical Research

Contact Info

Product

Resources

About