Application of allometric principles for the prediction of pharmacokinetics in human and veterinary drug development☆☆☆

Mahmood, Iftekhar

doi:10.1016/j.addr.2007.05.015

Cited by 146 publications

(152 citation statements)

References 36 publications

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“…Our data therefore raise well recognized issues relating to the choice of pre-clinical species for undertaking human PK predictions as well as the most appropriate allometric method for interspecies scaling [33][34][35][36][37]. The tendency for predictions of human CL to be over estimated by allometric scaling has been noted previously for several established drugs [34] and more recently for new chemical entities in microdose investigations [32].…”

Section: Figurementioning

confidence: 68%

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Ostenfeld

Beaumont

Bullman

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The microdose administration of novel drug candidates to humans in early development is currently undergoing evaluation as a cost‐efficient approach to the early assessment of pharmacokinetics (PK) before the commitment of resources required to support formal phase 1 studies.• The microdose approach assumes that PK can be extrapolated linearly over the full range of exposures achieved with sub‐pharmacological doses up to the therapeutic dose range.• Few microdose studies have been undertaken in the context of pharmaceutical drug development and their precise role in the selection of candidates for further clinical evaluation at therapeutic doses has yet to be fully substantiated.WHAT THIS STUDY ADDS• The present study describes the elective application of a human microdose study with a novel EP1 receptor antagonist, GSK269984A, to address a critical development liability posed by uncertainty with respect to the predicted human PK profile.• Microdose data revealed a favourable PK profile, consistent with a clinically acceptable dosing regimen. These data support the value of undertaking a microdose study early in the drug discovery process to facilitate risk evaluation and to enable decision‐making.AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography‐tandem mass spectrometry method following solid phase extraction.RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady‐state volume of distribution (Vss) and terminal elimination half‐life (t1/2) of GSK269984A were 9.8 l h−1, 62.8 l and 8.2 h. Cmax and AUC(0,∞) were 3.2 ng ml−1 and 10.2 ng ml−1 h, respectively; the corresponding oral parameters were 1.8 ng ml−1 and 9.8 ng ml−1 h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre‐clinical species (rat, dog and monkey).CONCLUSION For drug development programmes characterized by inconsistencies between pre‐clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

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Section: Figurementioning

confidence: 68%

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Ostenfeld

Beaumont

Bullman

et al. 2012

Brit J Clinical Pharma

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“…swissadme.ch/) yang dapat diakses secara publik untuk membantu relatif lebih mudah pemilihan senyawa yang memili "The Rule of Five" (Daina et al, 2017). Disisi lain, prediksi parameter farmakokinetik juga dapat dilakukan pada bidang veteriner sebagai tahap awal untuk uji pra-klinis bagi obat-obatan (Mahmood, 2007).…”

Section: Prediksi Parameter Farmakokinetikunclassified

Pemanfaatan bioinformatika dalam bidang pertanian dan kesehatan (The utilization of bioinformatics in the field of agriculture and health)

Parikesit

Anurogo

Putranto

2017

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“…Em virtude das diferenças encontradas entre os metabolismos dessas espécies, essas doses não demonstram a eficácia esperada. Nesse sentido, a extrapolação alométrica é uma alternativa que visa a adequar as doses pré-determinadas para espécies conhecidas aos animais que não passaram por tais experiências, levando em consideração o metabolismo entre as diferentes espécies (SEDGWICK, 1993;MAHMOOD, 2007). O método de cálculo por extrapolação alométrica leva em consideração a taxa metabólica basal, possibilitando a comparação entre animais de diferentes massas e grupos taxonômicos.…”

Section: O Objetivo Deste Estudo Foi Avaliar O Protocolo De Contençãounclassified

Associação de cetamina S(+) e midazolam pelo método convencional de cálculo e pela extrapolação alométrica em bugios-ruivo (Alouatta guariba clamitans): resposta clínica e cardiorrespiratória

et al. 2010

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O objetivo deste estudo foi avaliar o protocolo de contenção química com cetamina S(+) e midazolam em bugios-ruivos, comparando o cálculo de doses pelo método convencional e o método de extrapolação alométrica. Foram utilizados 12 macacos bugios (Alouatta guariba clamitans) hígidos, com peso médio de 4,84±0,97kg, de ambos os sexos. Após jejum alimentar de 12 horas e hídrico de seis horas, realizou-se contenção física manual e aferiram-se os seguintes parâmetros: frequência cardíaca (FC), frequência respiratória (f), tempo de preenchimento capilar (TPC), temperatura retal (TR), pressão arterial sistólica não invasiva (PANI) e valores de hemogasometria arterial. Posteriormente, os animais foram alocados em dois grupos: GC (Grupo Convencional, n=06), os quais receberam cetamina S(+) (5mg kg-1) e midazolam (0,5mg kg-1), pela via intramuscular, com doses calculadas pelo método convencional; e GA (Grupo Alometria, n=06), os quais receberam o mesmo protocolo, pela mesma via, utilizando-se as doses calculadas pelo método de extrapolação alométrica. Os parâmetros descritos foram mensurados novamente nos seguintes momentos: M5, M10, M20 e M30 (cinco, 10, 20 e 30 minutos após a administração dos fármacos, respectivamente). Também foram avaliados: qualidade de miorrelaxamento, reflexo podal e caudal, pinçamento interdigital, tempo para indução de decúbito, tempo hábil de sedação, qualidade de sedação, e tempo e qualidade de recuperação. O GA apresentou menor tempo para indução ao decúbito, maior grau e tempo de sedação, bem como redução significativa da FC e PANI de M5 até M30, quando comparado ao GC. Conclui-se que o grupo no qual o cálculo de dose foi realizado por meio da alometria (GA) apresentou melhor grau de relaxamento muscular e sedação, sem produzir depressão cardiorrespiratória significativa.

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Application of allometric principles for the prediction of pharmacokinetics in human and veterinary drug development☆☆☆

Cited by 146 publications

References 36 publications

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Pemanfaatan bioinformatika dalam bidang pertanian dan kesehatan (The utilization of bioinformatics in the field of agriculture and health)

Associação de cetamina S(+) e midazolam pelo método convencional de cálculo e pela extrapolação alométrica em bugios-ruivo (Alouatta guariba clamitans): resposta clínica e cardiorrespiratória

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