Role of Fixed Coefficients and Exponents in the Prediction of Human Drug Clearance: How Accurate are the Predictions from One or Two Species?

Mahmood, Iftekhar

doi:10.1002/jps.21597

Cited by 25 publications

(25 citation statements)

References 90 publications

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“…Thus, there has been considerable debate as to which power law to use, especially in interspecies scaling for first-in-human dosing. Some advocate that the best exponent to use is 2/3, some recommend 3/4, and yet others advocate a "floating" exponent (33)(34)(35). Work by several groups, including ours, has demonstrated that M 3/4 can also be applied to scale SCL of several antibiotics as weight changes within the human species, even specifically among adult patients (7,9,11,36).…”

Section: Discussionmentioning

confidence: 99%

Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures beyond Two-Thirds or Three-Fourths

Hall

Swancutt

Meek

et al. 2013

Antimicrob Agents Chemother

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Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergilllosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6) 3/4 . The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6) 3/2 , an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www .clinicaltrials.gov under registration number NCT01062165.) C aspofungin was the first echinocandin to be licensed and has enjoyed wide clinical success for treatment of candidiasis and aspergillosis over the past decades. There is now clear evidence of the superiority of echinocandins over azoles and polyenes for the treatment of candidemia, when both success rates and mortality are considered (1, 2). Nevertheless, the success rates with these agents are still around 70%. Thus, there is room to further improve outcomes; dose manipulation is one method for trying to improve treatment success. In order to achieve this, a greater understanding of population pharmacokinetics of caspofungin in the most frequently encountered types of patients is needed. Here, we examined the population pharmacokinetics of caspofungin, especially with relationship to patient weight.The human species is becoming more overweight and obese, with estimates that about 2 out of 9 billion people on the planet are obese (3-6). This unfortunate development means that overweight and obese people more and more characterize the usual patient encountered in hospitals all over the world. Candidiasis is one of the top five nosocomial infections and the most common fungal infection in hospitalized patients. Thus, echinocan...

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Section: Discussionmentioning

confidence: 99%

Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures beyond Two-Thirds or Three-Fourths

Hall

Swancutt

Meek

et al. 2013

Antimicrob Agents Chemother

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“…The prediction of drug clearance in humans using one preclinical species with fixed coefficients and exponents has been suggested to be an inappropriate method based on ~50 small molecules 15 and limited number of mAbs. 9 Due to the significant differences observed in the PK properties of mAbs and small molecules, we investigated the possibility of accurately estimating human PK of mAbs from monkey data using a fixed exponent.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data

Deng

Iyer

Theil

et al. 2011

mAbs

256

275

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“…32 Interspecies prediction study with one or two species conducted by Tang et al implied that the use of three or more species in allometric scaling was not necessary for the prediction of human CL. 33 On the contrary, the usefulness of multiple species scaling for prediction was demonstrated by some literatures, 34,35 and in particular, Goteti et al pointed out that the prediction from more than three species was far more accurate than two-species scaling. 34 In the present study, the ROE method, multiple species allometry, exhibited better predictivity than single species allometry.…”

Section: Discussionmentioning

confidence: 98%

Comparative Assessment of Empirical and Physiological Approaches on Predicting Human Clearances

Tamaki

Kono²,

Kogayu³

et al. 2011

Journal of Pharmaceutical Sciences

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Role of Fixed Coefficients and Exponents in the Prediction of Human Drug Clearance: How Accurate are the Predictions from One or Two Species?

Cited by 25 publications

References 90 publications

Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures beyond Two-Thirds or Three-Fourths

Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures beyond Two-Thirds or Three-Fourths

Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data

Comparative Assessment of Empirical and Physiological Approaches on Predicting Human Clearances

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