Sarah C. McLeay

The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007

AbstractBackground: A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size. Aim: The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL. Methods: Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a ‘nonlinear’ relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting ‘other’ relationships (e.g. linear increase in CL with TBW, ideal body weight or height). Results: A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)2/3, or estimated exponent of 0.646, i.e. ∼2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW. Conclusions: To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ∼2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size.

Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice

Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively. The sulfate anion transporter-1 (Sat1; also known as Slc26a1) mediates epithelial transport of oxalate and sulfate, and its localization in the kidney, liver, and intestine suggests that it may play a role in oxalate and sulfate homeostasis. To determine the physiological roles of Sat1, we created Sat1-/- mice by gene disruption. These mice exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder. Sat1-/- mice also displayed hypersulfaturia, hyposulfatemia, and enhanced acetaminophen-induced liver toxicity. These data suggest that Sat1 regulates both oxalate and sulfate homeostasis and may be critical to the development of calcium oxalate urolithiasis and hepatotoxicity.

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

ABSTRACT 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 (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/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 t1/2 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 Vc/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.

Anesthetizing the obese.

Why after 25 years of clinical use is there suddenly so much interest in propofol? Paracelsus wisely recognized that “the dose makes the poison,” and it makes you wonder if recent media reports have stirred up niggling reminders that propofol dosing is more of an art than a science. Part of this artistic license has resulted from the milligramper-kilogram dose, which attempts to normalize exposure across subjects of differing body size. However, since propofol’s approval, the world’s body composition has changed, with obesity prevalence in the United States’ adult population (classified as a body mass index [BMI] 30 kg/m) increasing from 13.4% in 1960 to 33.9% in 2008. What’s more, we’re getting bigger, prompting the World Health Organization to recategorize obesity into simple obesity (BMI 30–34.9 kg/m), severe obesity (35–39.9 kg/m), morbid obesity (40–49.9 kg/m), and super morbid obesity (BMI 40 kg/m). One must surely question whether dosing strategies developed in leaner populations remain applicable to today’s demography. For propofol, and other drugs, a body of research has questioned whether drug doses based on total body weight (TBW) can be reliably transported to the obese. If so, the following assumptions would need to be true: that volume of distribution, which defines initial drug dose, is twice as large for a 200-kg subject compared with a 100-kg subject and that clearance (CL), which determines maintenance dosing, is twice as fast in the respective 200-kg subject. The first assumption might not be unreasonable if the drug is lipid soluble and distributes into fat. However, for hydrophilic drugs, volume of distribution is more likely to be linearly related to lean body weight (LBW) rather than TBW. The second assumption, that CL is twice as fast in a 200-kg subject, seems implausible unless adipose tissue metabolizes the drug or the functional capacity of metabolizing organs, e.g., the liver and kidney, are linearly related to TBW. There is little evidence supporting this second assumption because 99% of metabolic processes occur within lean tissues. It is perhaps not too surprising then that CL seems best linearly related to LBW rather than TBW. The upshot in clinical practice is that subjects of different body compositions should expect a similar drug exposure if maintenance doses are determined on a milligram amount per kilogram of LBW. And here lies a challenge: LBW has been prohibitively difficult to use in the clinic, because accurate measurement via dual x-ray absorptiometry, for example, is not practical. Bioelectrical impedance analysis (BIA) is more readily available as demonstrated by Ingrande et al., although more frequently, equations developed by James in 1976 are used to estimate LBW. These equations cannot, however, be extrapolated to the obese because of numerical inconsistencies whereby LBW declines at certain weights and heights. New semimechanistic LBW equations developed in 2005 are transportable to the obese, with readers directed to the article by Janmahasatian et al. for a complete derivation. For propofol, there is clearly much confusion when dosing the obese, with most prior work unable to help anesthetists. The reason is that the obese have often been excluded from studies, or James’ LBW equations have been used to describe pharmacokinetic (PK) parameters. As such, CL has been reported to increase linearly with TBW or vary with some form of James’ LBW (Fig. 1). The empirical suggestion by Servin et al. of “corrected weight” was a possible metric that might be applicable to dosing the obese, although some have questioned its suitability in clinical practice. Trial design, subject population, and James’ LBW equations are responsible for the variety of relationships between TBW and CL shown in

Reporting a Population Pharmacokinetic–Pharmacodynamic Study: A Journal’s Perspective

The key purpose of performing pharmacometric research is to aid optimization of drug dosing strategies. The statistical techniques required for this research are advanced, which can make interpretation of results difficult to convey to the target audience if they are unfamiliar with pharmacometric concepts. This article provides a basic guide for authors who wish to publish pharmacometric analyses in peer-reviewed journals. This guide is intended to enhance the readability, reproducibility and understanding of the work for a general readership, which may include clinicians, pharmacists and pharmacometricians. Presentation techniques and examples are offered, as well as a checklist of suggested contents for the manuscript.

Noninvasive Quantification of Hepatic Steatosis: Relationship Between Obesity Status and Liver Fat Content

The aim of this study was to assess and compare fat content within the liver for normal (body mass index (BMI) < 25 kg/m 2 ), overweight (25-30 kg/m 2 ) and obese (� 30 kg/m 2 ) subjects using a noninvasive, non-contrast computed tomography (CT) quantification method. Adult subjects aged 18-60 yrs scheduled to undergo CT examination of the abdominal region were recruited for this study, stratified across BMI categories. Liver volume, fat content, and lean liver volume were determined using CT methods. A total of 100 subjects were recruited, including 30 normal weight, 31 overweight, and 39 obese. Total liver volume increased with BMI, with mean values of 1138 ± 277, 1374 ± 331, and 1766 ± 389 cm 3 for the normal, overweight, and obese, respectively (P < 0.001), which was due to an increase in both liver fat content and lean liver volume with BMI. Some obese subjects had no or minimal hepatic fat content. The prevalence of mild fatty liver in this study of 100 subjects was overestimated for all BMI categories using a range of qualitative diagnostic measures, with predicted prevalence of fatty liver in obese subjects ranging from 76.9% for liver-to-spleen ratio � 1.1 to 89.7% for liver attenuation index (liver HU - spleen HU) � 40, compared to 66.7% by quantification of fat content. Results show that total liver volume increases with BMI, however, not all obese subjects display fatty infiltration of the liver. CT quantification of liver fat content may be suitable for accurate diagnosis of hepatic steatosis in clinical practice and assessment of donor livers for transplantation.

Detailed Polysomnography in Australian Vietnam Veterans With and Without Posttraumatic Stress Disorder

STUDY OBJECTIVES Recent results from the PTSD Initiative, a cross-sectional cohort study in Australian Vietnam veterans (VV) with and without posttraumatic stress disorder (PTSD), demonstrated an increased prevalence of self-reported sleep disturbances in those with PTSD. This study aimed to objectively assess the prevalence of sleep disorders in the same cohort using detailed polysomnography (PSG). METHODS Participants from the PTSD Initiative were recruited to undergo PSG. PTSD status was determined with the Clinician Administered PTSD Scale for DSM-5 (CAPS-5). Subjective sleep information was attained via structured questionnaires. Data from single night PSG were compared between trauma-exposed VV with and without PTSD. RESULTS A total of 74 trauma-exposed male VV (40 with PTSD) underwent PSG (prospective n = 59, retrospective n = 15). All PSG parameters were similar between groups. No difference was seen in PSG-diagnosed obstructive sleep apnea (OSA) or periodic limb movements of sleep (PLMS). VV with PTSD showed a trend toward increased duration of sleep with oxygen saturations < 90% (10% versus 1.8%; P = .07). VV with PTSD reported increased sleep onset latency (42.4 versus 13.3 minutes; P < .01); were less likely to report sleeping well (32.5% versus 67.5%; P < .01); had higher OSA risk using Berlin Questionnaire (BQ) (70% versus 38.2%; P < .01); and had higher rates of partner-reported limb movements (56.4% versus 17.6%; P < .01). No association between PSG-diagnosed OSA and PTSD severity was evident. CONCLUSIONS In Australian VV with and without PTSD, no difference was seen across all PSG parameters including the diagnosis and severity of OSA and PLMS. However, VV with PTSD demonstrated an increased perception of sleep disturbances.

Sleep Disturbances in Australian Vietnam Veterans With and Without Posttraumatic Stress Disorder

STUDY OBJECTIVES Posttraumatic stress disorder (PTSD) is a condition that may develop after a traumatic event, particularly combat-related trauma. Although sleep disturbance is a hallmark of PTSD, the prevalence of sleep disturbances in Australian veterans with PTSD remains uncertain. This study aimed to subjectively compare the prevalence of sleep disturbances in Australian Vietnam veterans with and without PTSD. METHODS A cross-sectional cohort study compared trauma-exposed Australian Vietnam veterans with and without PTSD. PTSD diagnosis was confirmed using the Clinician Administered PTSD Scale for DSM-5. Sleep information was evaluated using supervised structured questionnaires, including Epworth Sleepiness Scale (ESS) and Berlin and Mayo Questionnaires. RESULTS Two hundred fourteen male Vietnam veterans (108 with PTSD) were included. Participants with PTSD had higher body mass index (30.3 versus 29 kg/m2; P < .05), higher ESS score (9.2 versus 7.6; P < .05), and increased alcohol or medication use to assist with sleep (19% versus 6%; P < .01; and 44% versus 14%; P < .01). Those with PTSD were less likely to sleep well (32% versus 72%; P < .01) and reported higher rates of restless legs (45% versus 25%; P < .01), nightmares (91% versus 29%; P < .01), nocturnal screaming (73% versus 18%; P < .01), sleep terrors (61% versus 13%; P < .01) and dream enactment (78% versus 11.8%; P < .01). The PTSD group had higher rates of diagnosed OSA (42% versus 21%; P < .01) and an increased risk of OSA on the Berlin Questionnaire (69% versus 43%; P < .01). CONCLUSIONS Compared to trauma-exposed controls, Australian Vietnam veterans with PTSD demonstrated an increased prevalence of a wide range of sleep disturbances, including OSA. In veterans with PTSD, detailed sleep assessment, including consideration of polysomnography, is paramount.