Informative study designs to identify true parameter–covariate relationships

Han, Phey Yen; Kirkpatrick, Carl M.; Green, Bruce

doi:10.1007/s10928-009-9115-y

Cited by 17 publications

(12 citation statements)

References 23 publications

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“…This result is in contrast to Svensson et al, who found an improvement in model fit when allometric scaling of disposition parameters with fixed coefficients were included (0.75 for clearances, 1 for volumes) (7). Our finding was not surprising, however, given the weak relationship observed between the eta for CL/F and size covariates, and a nonstratified distribution of weight, which can result in a lower probability of identifying a true covariate effect (18). It is likely in this case that the underlying covariate effect of weight was instead partially described by the lower CL/F observed for sicker MDR-TB patients than that for DS-TB patients and healthy volunteers.…”

Section: Discussionmentioning

confidence: 53%

Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

McLeay

Vis

Heeswijk

et al. 2014

Antimicrob Agents Chemother

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Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t 1/2 ). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (V c /F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t 1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and V c /F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

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Section: Discussionmentioning

confidence: 53%

Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

McLeay

Vis

Heeswijk

et al. 2014

Antimicrob Agents Chemother

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“…Hence, a pharmacokinetic modeler may easily conclude that a simple linear relationship exists between weight and clearance when the weight distribution of the study population is narrow. More detailed simulations that corroborate this simplistic example are provided in an excellent article …”

Section: Allometry and Drug Dosingmentioning

confidence: 64%

Drug Dosing Based on Weight and Body Surface Area: Mathematical Assumptions and Limitations in Obese Adults

Pai

2012

Pharmacotherapy

152

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The average weight of adults in the United States has increased by 25 pounds (11 kg) over the past 50 years, with a marginal change in height. Drugs are generally dosed according to one of three approaches: fixed dosing, weight-based dosing, or body surface area-based dosing. Dosing based on body weight or body surface area assumes that drug pharmacokinetic parameters increase in proportion with increasing body size. In contrast, dosing drugs on a fixed basis assumes that drug pharmacokinetic parameters do not increase with body size. Unfortunately, early stages of clinical drug development tend to include adults within a narrow range of body size. This study population does not reflect the current U.S. population distribution and does not permit evaluation of the correct relationship between body size and drug clearance. As a consequence, a weight-based or body surface area-based dosing regimen defined during drug development may not be applicable to U.S. patient populations. These dosing strategies are more likely to result in drug overexposure (weight-based approach) or underexposure (body surface area-based approach) among obese patients. Alternate weight descriptors such as ideal body weight, adjusted body weight, fat-free weight, and lean body weight are used to prevent drug overexposure with weight-based dosing, but their benefits and limitations must be understood. Reappraisal of the drug dosing paradigm is needed in this era of rising obesity; however, until drug-specific reviews can be performed, clinical studies must include patients at the extremes of the weight continuum to ensure applicable dose extrapolation for body size.

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“…The inclusion of this covariate in the present model is likely due to the wide, stratified distribution of body size descriptors in our study. Such a design has been suggested to increase the power to detect true covariate relationships (32).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

Justo

Mayer

Pai

et al. 2015

Antimicrob Agents Chemother

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The pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m 2 and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of >40 kg/m 2 compared to those <30 kg/m 2 . A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCL CR ) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is >90% when the MIC is <1 g/ml irrespective of TBW or eCL CR . No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCL CR . Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.) C eftaroline fosamil is a novel intravenously administered antimicrobial agent approved for use in the United States as a treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (1, 2). Unlike other regulatory approved cephalosporins, ceftaroline is uniquely active in vitro against methicillin-resistant Staphylococcus aureus (MRSA) (1-3). The current dosage regimen of ceftaroline fosamil is a fixed-dose of 600 mg every 12 h irrespective of body size in adult patients. Upon administration, the prodrug ceftaroline fosamil is converted by phosphatases to the active form ceftaroline that is principally (60%) eliminated unchanged in urine and to a small (6%) extent as an inactive metabolite (ceftaroline-M1). The dose should be reduced in patients with renal impairment when the estimated creatinine clearance (eCL CR ) is Յ50 ml/min.Obesity is defined as a body mass index (BMI) of Ն30 kg/m 2 and has been independently associated with an increased risk of certain infections such as ABSSSIs (4-6). Some evidence suggests obese patients may be at risk of worse clinical outcomes attributed in part to ina...

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Informative study designs to identify true parameter–covariate relationships

Cited by 17 publications

References 23 publications

Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

Drug Dosing Based on Weight and Body Surface Area: Mathematical Assumptions and Limitations in Obese Adults

Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

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