Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion

Hummel, Jürgen; McKendrick, Sue; Brindley, Charlie; French, Raymond

doi:10.1002/pst.326

Cited by 143 publications

(119 citation statements)

References 58 publications

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“…Subject characteristics and pharmacokinetic parameters are expressed as mean and standard deviation. A nonlinear power model was used to assess dose proportionality: parameter ϭ a ϫ dose b , where a is a constant, b is the proportionality constant, and parameter is C max or AUC 0-ϱ (12). Log transformation of the equation results in a linear equation: log a ϩ b ϫ log dose.…”

Section: Subjectsmentioning

confidence: 99%

Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

Beringer

Owens

Nguyen

et al. 2012

Antimicrob Agents Chemother

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Section: Subjectsmentioning

confidence: 99%

Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

Beringer

Owens

Nguyen

et al. 2012

Antimicrob Agents Chemother

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“…The dose proportionality of LPZ could not be concluded with the equivalence criterion of (0.8, 1.25). However, the bioequivalence criterion of (0.8, 1.25) was reasonable for dose levels only a doubling apart but impractically strict when applied over the complete dose range, for which a wider criterion of (0.5, 2) was more suitable (Hummel et al 2009). Hence, LPZ displayed linear PK in healthy Chinese subjects after single i.v.…”

Section: Discussionmentioning

confidence: 97%

“…In recent years, more and more researches used the power model combined with a criterion based on comparing the 90% CI for the ratio of predicted mean values from the extremes of the dose range to predefined equivalence criterion (θ L , θ U ) to evaluate the dose proportionality (Hummel et al 2009). The dose proportionality of LPZ could not be concluded with the equivalence criterion of (0.8, 1.25).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of lansoprazole and its main metabolites after single intravenous doses in healthy Chinese subjects

et al. 2012

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The aim of the study was to evaluate the pharmacokinetics (PK) of lansoprazole (LPZ) and its main metabolites 5'-hydroxy lansoprazole (HLPZ) and lansoprazole sulphone (LPZS) after single intravenous (i.v.) doses of LPZ in healthy Chinese subjects, and the relationship between the cytochrome P450 (CYP) 2C19 phenotypes and the plasma concentrations of LPZS at the time-points in the elimination phase of LPZ. Twelve subjects were given lansoprazole by i.v. infusion. Blood samples were collected at designated time points up to 24 h. Plasma concentrations of LPZ, HLPZ and LPZS were quantified by a selective and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. After single i.v. doses of 15, 30 and 60 mg LPZ, C(max) and area under the plasma concentration-time curve (AUC(0-t)) of LPZ were 725 ± 151, 1480 ± 190, 3130 ± 480 µg · L(-1) and 1690 ± 1210, 3630 ± 2530, 8080 ± 4550 µg · h · L(-1), respectively. LPZ was generally well tolerated in healthy Chinese subjects, and displayed linear PK in the range of 15-60 mg. There were significant differences in the elimination of LPZ and the formation of LPZS between the single CYP2C19 poor metabolizer (PM) and the CYP2C19 extensive metabolizers (EM). The concentration of LPZS at the time-points in the elimination phase of LPZ could be monitored for CYP2C19 phenotyping. As a probe drug for CYP2C19 phenotyping, LPZ for injection might be more suitable than LPZ oral formulations.

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“…There may be a reporting bias regarding the presence of nonlinearities. On the other hand, although the statistical method to establish non-linearities may differ between studies [74], the most widely used criterion for non-linearities in ascending-dose studies is a deviation outside the range of a factor 0.8-1.25 [75]. For the prediction of pharmacokinetics in the preclinical stage, this criterion is unnecessarily strict.…”

Section: Discussionmentioning

confidence: 99%

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

Bosgra¹,

Vlaming²,

Vaes³

2015

Clin Pharmacokinet

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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.

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Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion

Cited by 143 publications

References 58 publications

Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

Pharmacokinetics of lansoprazole and its main metabolites after single intravenous doses in healthy Chinese subjects

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

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