Animal-to-Human Extrapolation of the Pharmacokinetic and Pharmacodynamic Properties of Buprenorphine

Yassen, Ashraf; Olofsen, Erik; Kan, Jingmin; Dahan, Albert; Danhof, Meindert

doi:10.2165/00003088-200746050-00005

Cited by 36 publications

(22 citation statements)

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“…Based on allometric principles biological time periods, t, are dependent on a scaling factor in the power function of ¼ (t=θ · body weight 1/4 ) [11]. Although there has been a clear correlation to body weight in scaling pharmacodynamic models [15][16][17][18][19] the estimates of the exponent of the correlation have in most cases differed from the theoretical value of ¼. Interestingly, the exponent for red blood cell and red blood cell precursor life spans were estimated to 0.124-0.148 [15], which is similar to the exponent value of 0.158 that would be used to scale the here estimated MTT for white blood cells of 52.8 h in a 300 g rat to a value of 125 h in a 70 kg patient. The estimated feedback factor γ was 0.149 in rats, a value that is in the same range as those earlier determined in patients (0.121-0.239) [1].…”

Section: Discussionmentioning

confidence: 99%

“…Model-based pharmacodynamic scaling has for example been performed for recombinant human erythropoietin [15], 5-Ht 1A receptor mediated responses, i.e. hypothermia and cortisol responses [16], respiratory depressant and antinociceptive effects [17], thromboxane B 2 and prostaglandin E 2 dynamics [18] and muscle relaxation [19]. The low number of successful cases of pharmacodynamic scaling may partly be because often parameters used in the scaling are based on empirical models in contrast to physiologybased or mechanistic models.…”

Section: Introductionmentioning

confidence: 99%

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Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

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“…This approach confers advantages in that the structure and parameters of the model can be related to prior mechanistic data, the concentration response can be related to any in vitro measures of pharmacology, and extrapolation of preclinical findings to the clinical outcome can in principle be facilitated. For example, a mechanistic PK-PD approach was used previously to show that buprenorphine-specific PD parameters such as binding of the drug to the target were similar in rats and humans (40). In addition, it has been found that although concentration-response data can translate well between species, the dose response can be very different due to interspecies PK differences (23).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

Benson

Jongh²,

Duckworth

et al. 2010

Antimicrob Agents Chemother

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Recombinant alpha interferon (IFN-␣) is used in the treatment of hepatitis C virus (HCV)-infected patientsbut is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-␣ and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-␣ as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.An estimated 200 million people worldwide (39) are infected with hepatitis c virus (HCV). The virus replicates primarily in the liver, and 70% of those infected go on to develop chronic infection, with a further 20% progressing to serious liver disease (6). The current standard of care for HCV infection is treatment with pegylated alpha interferon (IFN-␣) combined with ribavirin; however, this treatment is effective for less than 50% of patients (26). Furthermore, significant side effects, including flu-like symptoms, depression, injection site reactions, and hemolytic anemia, are observed (10). The need to develop more available, better-tolerated, and more effective medicines is therefore clear. To this end, one of the areas of interest has been the targeting of IFN inducers (13, 18) and specifically Toll-like 7 receptor (TLR-7) agonists (9). The TLR family plays a critical role in the innate immune response via recognition of pathogen-associated molecular patterns (PAMPs). These are conserved and essential to viability. TLR-7 itself is thought to be endosomally located and to recognize and bind single-stranded RNA. This results in the induction of type I IFN production, including a robust IFN-␣ response, leading in turn to an antiviral effect. This response has been described previously as recognizing abnormal localization of nucleic acid rather than structures or motifs absent from the host (reference 7; for a review, see also reference 8).Although the hypothesis supporting the development of TLR-7 agonists as novel drugs appears to be sound, the behavior of a given drug in the in vivo system is often very hard to predict, leading to attrition due to lack of efficacy or safety concerns (20). As a means to address this issue quantitatively, biomarker and translational pharmacology approaches (25) and modeling-and simulation-based drug development (22, 37) are being explored as ways forward. To develop an improved understanding of translational pharmacology, biomarkers of efficacy that are present both in preclinical species and in humans would be highly valuable. A number of potential biomarkers of relevance for HCV have been reported previously (see, e.g., references 1, 16, and 38). Of these biomarkers, IFN-␣ is attractive as it is readily measurable in preclinical species and humans by commercia...

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“…Allometric scaling of drug pharmacokinetic properties and biological system-specific parameters has been used in translational investigations, with reasonable degree of success, to predict drug effects in humans (Yassen et al 2007;Zuideveld et al 2007). But, pharmacodynamic properties are more difficult to scale compared to pharmacokinetic properties, since pharmacodynamic parameters are often not related to bodyweight (e.g., receptor (Kvernmo et al 2006(Kvernmo et al , 2008 and on prolactin in animals and human (Ben Jonathan et al 2008).…”

Section: Use Of the Structural Preclinical Pkpd Model To Finally Predictmentioning

confidence: 99%

PKPD Aspects of Brain Drug Delivery in a Translational Perspective

Lange

2013

Drug Delivery to the Brain

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The development and optimization of CNS drug is hampered by the inaccessibility of the human brain and the difficulty to quantify human CNS drug effects. The use of serial CSF sampling in animals and mathematical modeling of plasma pharmacokinetics, in conjunction with CNS effects, provided only useful information for drugs that distribute to the brain target site by simple diffusion and having direct and reversible CNS effects. Active transport processes across bloodbrain barriers and brain cell membranes may be applicable for many drugs and should be taken into account. Also, context dependencies of the rates and extents of all transport processes should be included. This indicates the need for crosscompare designed preclinical experimental approaches and mathematical modeling to provide information on contributions of the (main) individual processes, in terms of rate and extent, as well as their interplay, to be able to predict human CNS drug effects. Abbreviations ARAgonist receptor complex density BBB Blood-brain barrier BCSFB Blood-cerebrospinal fluid barrier Ce Concentration of the drug in the effect compartment CNS Central nervous system CSF Cerebrospinal fluid E Effect

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Animal-to-Human Extrapolation of the Pharmacokinetic and Pharmacodynamic Properties of Buprenorphine

Abstract: The different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid mu receptor subtypes involved in the antinociceptive and respiratory depressant effects.

Cited by 36 publications

References 22 publications

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

PKPD Aspects of Brain Drug Delivery in a Translational Perspective

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