Obesity is a serious condition with many known comorbid conditions and other health risks. Despite the rising global rates of obesity, drug disposition in this population is typically understudied, which results in limited information guiding the use of drugs in patients with obesity. Presently, dosing adjustments for patients with obesity typically focus on addressing altered drug clearance with body size and are therefore limited to chronic dosing recommendations. These instructions are variable and rarely based on dedicated studies in people with obesity. This review briefly discusses the current clinical use of body measurements to guide chronic dosing instructions and highlights the need for obesity-specific dosing instructions when the half-life of a drug is prolonged (typically through increased volume of distribution) in people with obesity. Examples of drugs with apparent opportunities for either ramp-up, loading, or washout instructions for patients based on body mass index are identified, specifically for vortioxetine, posaconazole, and brexpiprazole. We call for inclusion of people with obesity in clinical studies as a special subpopulation during drug development and propose the use of body mass index to guide dosing decisions among these patients.

Dual‐energy x‐ray absorptiometry (DXA) scanning is used for objective determination of body composition, but instrumentation is expensive and not generally available in customary clinical practice. Anthropometric surrogates are often substituted as anticipated correlates of absolute and relative body fat content in the clinical management of obesity and its associated medical risks. DXA and anthropometric data from a cohort of 9230 randomly selected American subjects, available through the ongoing National Health and Nutrition Examination Survey, was used to evaluate combinations of surrogates (age, height, total weight, waist circumference) as predictors of DXA‐determined absolute and relative body fat content. Multiple regression analysis yielded linear combinations of the 4 surrogates that were closely predictive of DXA‐determined absolute fat content (R 2 = 0.93 and 0.96 for male and female subjects). Accuracy of the new algorithm was improved over customary surrogate‐based predictors such as body mass index. However prediction of relative body fat was less robust (R 2 less than 0.75), probably due to the nonlinear relation between degree of obesity (based on body mass index) and relative body fat. The paradigm was validated using an independent cohort from the National Health and Nutrition Examination Survey, as well as two independent external subject groups. The described regression‐based algorithm is likely to be a sufficiently accurate predictor of absolute body fat (but not relative body fat) to substitute for DXA scanning in many clinical situations. Further work is needed to assess algorithm validity for subgroups of individuals with “atypical” body construction.

In 1979, the late Dr. Darrell R. Abernethy and colleagues began a series of clinical studies aimed at understanding the pertinent determinants of drug distribution, elimination, and clearance in obesity, and how those variables are interconnected. The studies confirmed that volume of distribution (V d ) and clearance are the principal independent biological variables, which conjointly determine elimination of half‐life as a dependent variable. For drugs distributed by passive diffusion, their pharmacokinetic V d — after correcting for plasma protein binding — was increased in obesity, depending in part on the physicochemical lipophilicity of the individual drugs, and the quantitative extent of obesity in overweight individuals. Across all studies, the ratio of mean clearance in obese divided by control groups had an overall median value of 1.21 (range, 0.75‐3.11), indicating a small and variable effect of obesity on clearance, without clear directionality. Since drug clearance was not clearly related to lipophilicity or degree of obesity, the prolonged half‐life of lipophilic drugs in patients with obesity was largely explained by the increased V d . Dr. Abernethy further identified delayed attainment of steady state after initiation of multiple‐dose treatment, and delayed washout after termination of dosage, as potential clinical consequences of the extended half‐life in people with obesity. These consequences for specific drugs have been recently emphasized in contemporary studies of chronic dosage in subjects with obesity. Without data identifying an obesity‐related change in clearance for a specific drug, maintenance doses (in milligrams) should be based on ideal weight rather than adjusted upward on the basis of total weight.

OBJECTIVES:Acetaminophen (APAP) (paracetamol) is a widely used non-prescription drug for pain relief and antipyretic effects. The clearance of APAP is mainly through phase-2 biotransformation catalysed by UDP-glucuronosyl transferases (UGT). Dasabuvir is an anti-hepatitis C drug reported to inhibit several UGT isoforms. The study evaluated the in-vitro inhibitory capacity of dasabuvir versus APAP glucuronidation.METHODS:Procedures included human liver microsomal incubations with APAP and isoform-selective probe substrates.KEY FINDINGS:Dasabuvir inhibited APAP metabolism by a reversible, mixed-type (competitive and non-competitive) partial inhibition, with an inhibition constant Ki = 3.4 µM. The index constant 'a' was 6.7, indicating the relative contribution of competitive and non-competitive inhibition. The enzyme-inhibitor complex was still able to catalyse the reaction by 12% of the control capacity. Dasabuvir produced strong partial inhibition effect of UGT1A1 and UGT1A9 and relatively complete inhibition of UGT1A6.CONCLUSIONS:Consistent with previous reports, dasabuvir inhibits the activity of 3 UGT isoforms associated with APAP metabolism. In-vitro to in-vivo scaling by 2 different approaches showed identical results, predicting an increased AUC of APAP by a factor of 1.3-fold with coadministration of dasabuvir. Until the findings are confirmed in clinical drug interaction studies, APAP dosage should not exceed 3 g per day in dasabuvir-treated patients to avoid potentially hepatotoxic APAP exposures.

AIMS:For a given passively-distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, Vd ) in obese individuals increases in relation to the degree of obesity. The present study had the objective of evaluating drug distribution in relation to in vitro lipophilicity, and the relative increase in Vd associated with obesity across a series of drugs.METHODS:Cohorts of normal-weight control and obese subjects received single doses of drugs ranging from hydrophilic (acetaminophen, salicylate) to lipophilic (imipramine, verapamil). Lipid solubility was measured by the log-transformed values of the high-pressure liquid chromatographic (HPLC) retention index (Log10 (HPLC)), and the octanol-water partition coefficient (LogP).RESULTS:Among normal-weight controls, Vd normalized for protein binding was highly correlated with Log10 (HPLC) (R2 = .65) and with LogP (R2 = .78). Vd of all drugs was increased in the obese cohort, but the relative increase (compared to controls) for individual drugs was disproportionately greater as lipid solubility increased. Since clearance was unrelated to lipophilicity, the increased Vd produced a parallel disproportionate increase in elimination half-life in the obese cohort that was associated with Log10 (HPLC) (R2 = .62).CONCLUSION:Lipophilicity is a principal correlate of in vivo Vd , as well as the increased Vd of drugs in obese patients. The consequent prolongation of half-life in obesity has clinical safety implications in terms of delayed drug accumulation and washout during and after chronic dosage. The magnitude and importance of this effect for a given drug depends on the degree of obesity, as well as the lipid-solubility of the specific drug.

Age-related changes in disposition of diazepam and its principal active metabolite, desmethyldiazepam (DMDZ), during and after extended dosage with diazepam were studied in healthy volunteers. Eight elderly subjects (ages 61-78 years) and 7 young subjects (21-33 years) received 2.5 mg of diazepam twice daily for 15 days. Predose (trough) concentrations of diazepam and DMDZ were measured during the 15 days of dosing, and in the postdosage washout period. Kinetic properties were determined by nonlinear regression using a sequential drug-to-metabolite pharmacokinetic model. Steady-state plasma concentrations of diazepam and DMDZ were 30% to 35% higher in elderly subjects compared to young volunteers, and steady-state clearances correspondingly lower, though differences did not reach significance. Large and significant differences were found between young and elderly groups in mean half-life of diazepam (31 vs 86 hours; P < .005) and DMDZ (40 vs 80 hours; P < .02). Half-life values from the multiple-dose study were closely correlated with values from previous single-dose studies of diazepam (R2 = 0.85) and DMDZ (R2 = 0.94) in the same subjects. With extended dosing of diazepam in the elderly, slow accumulation and delayed washout of diazepam and DMDZ is probable. After discontinuation, withdrawal or rebound effects are reduced in likelihood, but delayed recovery from sedative effects is possible due to slow elimination of active compounds. Safe treatment of elderly patients with diazepam is supported by understanding of age-related changes in pharmacologic and pharmacokinetic properties.

From Tufts University School of Medicine, Boston, MA. Reprints: David J. Greenblatt, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111 (e-mail: [email protected]).

Background In 2013 the Food and Drug Administration (FDA) claimed the existence of new data showing women to be at risk for excessive daytime sedation and impaired driving proficiency following bedtime doses of zolpidem. The putative explanation was the reduced metabolic clearance of zolpidem and higher morning blood concentrations in women compared to men. The FDA acted to reduce the recommended dosage for women down to 50% of the dose for men. No other regulatory agency worldwide has taken similar action. Methods Gender effects on zolpidem pharmacokinetics, pharmacodynamics, adverse effects, clinical efficacy, and driving performance were evaluated through a further analysis of data from a previous study, together with a literature review. Results Women had on average 35% lower apparent clearance of zolpidem than men (236 vs 364 mL/min, P < 0.001). This difference was not explained by body weight. In some laboratory studies, women had greater functional impairment than men taking the same dose, but in all studies active drug was not distinguishable from placebo at 8 hours after oral dosage. On-the-road driving studies likewise showed no evidence of driving impairment in men or women at 8 hours after 10 mg of oral immediate-release zolpidem. No clinical trial demonstrated a gender-related difference in clinical efficacy or adverse reactions, and there was no evidence of a particular risk to women. Conclusions Dosage reduction in women is not supported by available scientific evidence, and may in fact lead to underdosing and the consequent hazard of inadequately treated insomnia.

Purpose/Background: The antipsychotic agent lurasidone (Latuda (R)) is metabolized by Cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors (such as ketoconazole, posaconazole, and ritonavir) is contraindicated due to the risk of sedation and movement disorders from high levels of lurasidone. This study evaluated the time-course of recovery from the posaconazole drug interaction, and the effect of obesity on the recovery process. Methods/Procedures: Healthy normal-weight volunteers (n = 11, mean body mass index, BMI, = 23.1 kg/m(2)) and otherwise healthy obese subjects (n = 13, mean BMI = 49.3 kg/m(2)) received single doses of lurasidone in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. Findings/Results: With posaconazole coadministration, lurasidone area under the concentration curve (AUC) increased by an arithmetic mean factor of 6.2 in normals, and by 4.9 in obese subjects. Post-treatment washout of posaconazole was slow in normals (mean half-life 31 hours), and further prolonged in obese subjects (53 hours). Recovery of lurasidone AUC toward baseline was correspondingly slow, and was incomplete. AUC remained significantly elevated above baseline both in normals (factor of 2.1) and obese subjects (factor of 3.4) even at 2 weeks after stopping posaconazole. Implications/Conclusions: Product labeling does not address the necessary delay after discontinuation of a strong CYP3A inhibitor before lurasidone can be safely administered. We recommend requiring normal-weight and obese patients to limit the dosage of lurasidone, or undergo a washout period, for two and three weeks, respectively, after discontinuation of posaconazole.

The antianginal agent ranolazine (Ranexa®) is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. With posaconazole coadministration, the geometric mean ratio of ranolazine area under the concentration curve (AUC) increased by a factor of 3.9 in normals and by 2.8 in obese subjects. Posttreatment washout of posaconazole was slow in normals (mean half-life 36 hours) and further prolonged in obese subjects (64 hours). Recovery of ranolazine AUC toward baseline was delayed. AUC remained significantly elevated above baseline in normal-weight and obese subjects for 7-14 days after stopping posaconazole. Current product labeling does not address the need for delay or a reduced dose of ranolazine after discontinuation of a strong CYP3A inhibitor before ranolazine can be safely administered. We recommend that administration of ranolazine should be limited to 500 mg twice daily for 7 days after posaconazole discontinuation in patients with body mass index 18.5-24.9 kg/m2 and for 12 days in patients with body mass index ≥35 kg/m2 after ranolazine is resumed.

Background: Obesity and depression are common comorbid conditions. The objective of the study was to evaluate the effect of obesity on the pharmacokinetics of the serotonergic antidepressant vortioxetine. Methods: Vortioxetine pharmacokinetics were evaluated in 16 otherwise healthy obese volunteers (mean weight, 119 kg; mean body mass index (BMI) 41.8 kg/m(2)) and in 14 normal-weight subjects (mean weight, 68 kg; mean BMI, 23.0 kg/m(2)) matched for age. All subjects received a single 5-mg oral dose of vortioxetine once daily for 29 days. Pre-dose plasma vortioxetine concentrations were measured during the 29 days of dosing, and during a 4-week washout period after the last dose. Full 24-hour profiles were obtained after the first and last doses. Results: Vortioxetine accumulated extensively over the 29 days; the accumulation ratio was not significantly different between obese and control groups (means: 5.24 and 4.46, respectively). Steady-state concentration (C-ss) and steady-state clearance also did not differ between groups. However mean washout half-life (T-1/2) was significantly prolonged in obese vs. control subjects (3.26 days vs. 2.21 days, P < 0.01). Up to 89% of the individual variability in T-1/2 was explained by the product of C-ss and numeric indicators of the degree of obesity. Conclusions: The half-life of vortioxetine washout after discontinuation of therapy is significantly prolonged in obese individuals compared to normal weight controls. To avoid a potential risk of serotonin syndrome, obese patients who plan to change their medication from vortioxetine to a monoamine oxidase inhibitor (MAOI) should extend the time between vortioxetine discontinuation and MAOI initiation beyond what is recommended in the product label.

Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P‐glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age‐matched controls with normal renal function were studied concurrently. Subjects’ overall mean age was 59 years. Mean creatinine clearance values in the 2 groups were 105 and 71 mL/min. After single 20‐mg oral doses, rivaroxaban area under the curve (AUC) was increased by a factor of 1.11 (ratio of geometric means [RGM]) in mild renal insufficiency compared to controls. Verapamil coadministration independently increased AUC to the same extent in both the mild renal insufficiency and control groups (RGM, 1.39 and 1.43). Concurrent mild renal insufficiency and verapamil produced additive inhibition compared to controls without verapamil (RGM, 1.58). Prothrombin time (PT) prolongation and Factor Xa inhibition tracked plasma rivaroxaban, and were enhanced by verapamil. Concentration–response relationships for PT (linear) and Factor Xa inhibition (hyperbolic) were unaffected by renal function or verapamil. The absolute and relative increases in rivaroxaban AUC caused by verapamil in mild renal insufficiency subjects are potentially associated with an increased bleeding risk. Modification of recommended dosage may be required in this combination of circumstances to reduce risk to patients.

OBJECTIVES:Resveratrol is a naturally occurring antioxidant with therapeutic potential in prevention and treatment of neoplastic disease and other human disorders. However, net clearance of resveratrol in humans is very high, mainly due to glucuronide conjugation. This leads to extensive presystemic extraction and low plasma concentrations after oral dosage. The present study evaluated the effect of probenecid, an inhibitor of glucuronide conjugation, on resveratrol metabolism in vitro. METHODS:Biotransformation of resveratrol to its 3-O-glucuronide and 4'-O-glucuronide conjugates was studied in vitro using human liver microsomal preparations. The mechanism and inhibitory potency of probenecid were evaluated based on a mixed competitive-noncompetitive inhibition model. KEY FINDINGS:Probenecid inhibition of resveratrol 3-O-glucuronidation was predominantly noncompetitive, with an inhibition constant (Ki ) averaging 3.1 mm. CONCLUSIONS:The ratio of in vivo maximum concentration of probenecid [I] during usual clinical use to the in vitro Ki value ([I]/Ki ) exceeds the boundary value of 0.1, used by regulatory agencies to identify the possibility of clinical drug interactions. This finding, together with the known property of probenecid as an inhibitor of glucuronide conjugation in humans, suggests that probenecid could serve as a pharmacokinetic boosting agent to enhance systemic exposure to resveratrol in humans.

Our February, 2011 editorial in these pages analyzed psychotropic drug prescribing patterns in the United States for calendar year 2009.1 This analysis included data on numbers of outpatient retail prescriptions for individual psychotropic drugs and drug classes, along with information on costs and expenditures. The principal data source at that time was “SDI/Verispan, VONA.” The information was provided to and subsequently published on an annual basis by Drug Topics, and included listings of the top 200 prescription drugs, with separate lists for generic and brand-name drugs, and rankings according to number of prescriptions as well as dollar sales revenue. More than 5 years have elapsed, and we have updated our analysis of psychotropic drug prescribing patterns, anticipating that the landscape might have changed in significant ways. New drug entities have become available, many brand-name drugs have become generic, and some drug entities have been approved for new indications or with new dosage forms. Over the same time interval, the corporate landscape has also changed, and the extensive listings described above are no longer available. More limited listings can be obtained via sources such as Statista.com, Medscape.com, Drugs.com, and IMS Health, but none is comparable to what was available for our previous review. For the present analysis, we identified two potential sources of outpatient retail prescription data: Symphony Health Solutions Corp., and ClinCalc.com/DrugStats. Symphony covers calendar year 2014, and ranks the top 200 drugs by number of prescriptions. ClinCalc ranks the top 300 for a 12-month period from mid-2014 to mid-2015. The two sources provide similar but not identical prescription numbers for individual drugs, with Symphony estimates being on average 26% higher than those from ClinCalc. Because ClinCalc included more drugs in their ranking, we used this source for our subsequent analysis. The ClinCalc data comes from the annual Medical Expenditure Panel Survey (MEPS), a survey conducted by the Agency for Healthcare Research and Quality, a federal agency. All data is publicly available at no cost on the MEPS web site. Neither ClinCalc nor Symphony provides data on expenditures or sales. To acquire cost information, we used Data-Rx.com, which gives retail costs of all marketed brand-name and generic prescription drugs. We assumed that a typical prescription contained 100 dose units, and calculated total expenditures for that drug as the product of number of prescriptions multiplied by the cost of the typical prescription. In our earlier analysis, this calculation method yielded expenditure estimates that were close to the actual expenditures available at that time from the data base.1 With only 2 exceptions (vilazodone and lurasidone), all drugs on the list were available as generics, and most of those continued to be obtainable as the original brand names as well (Table 1). The lower generic cost was used for the expenditure estimates, and we calculated a brand/generic cost ratio when both were available. Note that we did not include stimulants, analgesics, anticonvulsants, or GABAergic drugs (gabapentin, pregabalin) in the analysis, and no information was available on drugs that did not fall into the top 300. Among drugs not represented on the list are newer agents (suvorexant, vortioxetine, paliperidone, and others), as well as older drugs (clozapine, chlordiazepoxide, triazolam, lithium, monoamine oxidase inhibitors, and others).TABLE 1: Psychotropic Drug Prescribing in the United States, 2014–2015Total psychotropic drug prescriptions for the target one-year period were just under 380 million. Of these, only 3.2 million (0.8% of the total) were accounted for by the 2 brand-name drugs; the rest were generic (Tables 1 and 2). Consistent with our previous report1 and data from other sources,2 antidepressants accounted for 58% of all prescriptions (Fig. 1). Anxiolytics, hypnotics, and antipsychotics accounted for 22%, 15%, and 5% of prescriptions, respectively. Total estimated expenditures were $29,667 million, which were not proportionately distributed between generic and brand-name drugs. Expenditures for vilazodone and lurasidone together amounted to $6,901 million – 23% of total psychotropic prescription expenditures – though these 2 drugs accounted for less than 1% of total prescriptions.TABLE 2: Summary of Psychotropic Drug Prescribing, Costs, And ExpendituresFIGURE 1: Outpatient prescriptions for antidepressants, anxiolytics, hypnotics, and antipsychotics in the United States, 2014–2015. See Tables 1 and 2 for detailed data.Antidepressant prescribing was largely comprised of serotonin reuptake inhibitors and mixed-mechanism agents (Table 1). Amitriptyline continues to be extensively used, with annual prescriptions exceeding 10 million. With the exception of vilazodone, all antidepressants on the list were available generically, with a mean cost per generic prescription of $57.13. However the arithmetic mean was biased by some high outlying values (Table 1). The brand/generic cost ratio averaged 8.1, with a wide range (1.4 to 15.8) (Tables 1 and 2). Benzodiazepine anxiolytics3 continue to be widely prescribed, accounting for more than 75 million prescriptions during the target time period (Table 1). Alprazolam prescriptions were 39% of this total. All 4 benzodiazepines on the list were generic drugs, with an average cost per prescription of $16.12. It is of interest that the overall extent of benzodiazepine prescribing in the present analysis is very close to the estimate of 80 to 90 million in the mid-1970s4,5 – numbers which elicited concern and alarm.6–8 Hypnotic prescriptions exceeded 55 million. Based on data from a number of sources,9–14 trazodone is used principally as a hypnotic though not specifically indicated for this purpose,15,16 and we categorized trazodone as such. Trazodone accounted for 46% of hypnotic prescriptions, with zolpidem17 (immediate-release and modified-release together) accounting for 38%. All hypnotics in the survey were available generically, at consistently low cost. The evident limitation of the antipsychotic prescribing data is that medication usage in non-retail settings (hospitals, clinics, and institutions) are not captured. In the setting of outpatient retail prescribing addressed in the present analysis, antipsychotics (except lurasidone) were available generically, though the generic prescriptions were substantially more expensive than those in the other drug categories. The cost of brand-name lurasidone (Latuda) was eye-catching, with each individual dose unit costing nearly $38.00 in a prescription of 100. Psychotropic medication prescribing and use are increasing yearly,2,18 reflecting the continuous increase in the population size, and the collective determination to destigmatize mental illness and use treatment options to improve quality of life. Our comment in 1975,19 which remains applicable today, noted that studies of medication prescribing numbers by themselves “ … do not provide a sole or adequate definition of treatment option, need, or efficacy.” A COMMENT ON VILAZODONE As noted above, all antidepressants, with the exception of vilazodone, were available as generics. Once drugs become generic, both direct-to-consumer advertising and clinician-office detailing taper off. At the time of FDA approval of vilazodone in 2011, FDA staff wrote that there was no evidence in the submitted data to suggest that it had “…any advantages compared to other drugs in the antidepressant class.”20 When outpatients suffering from moderate to severe depression were treated with vilazodone or placebo, about one quarter achieved clinical remission on vilazodone compared to 18% receiving placebo.21–23 Given the relatively high cost of vilazodone (Tables 1 and 2), its adoption by clinicians might bear a direct relationship to detailing and advertising. In 2017, the cost for a one-month prescription for vilazodone ranged from $231.78 and $246.99 compared to a one-month supply of sertraline ($8.70 to $27.99).24 There is no evidence to suggest that vilazodone will succeed where other antidepressants have failed.

Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African-Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; P = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; P < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; P < 0.001) and glucuronidation partial clearance (by 23-48%; P < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; P = 0.003) and *1/*1 (by 41%; P = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; P = 0.041) and *1C/*1C (by 44%; P = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans.

CONTEXTCollegiate football programs encourage athletes to pursue high body weights.OBJECTIVETo examine position-dependent trends over time in body size characteristics among football players in the National Collegiate Athletic Association Division III New England Small College Athletic Conference (NESCAC) from 1956 to 2014 and to compare the observed absolute and relative changes with those in age-matched male population controls.DESIGNDescriptive laboratory study.SETTINGMedical school affiliated with a NESCAC institution.PATIENTS OR OTHER PARTICIPANTSFootball team rosters from the 10-member NESCAC schools, available as public documents, were analyzed along with body size data from general population males aged 20 to 29 years from the National Health and Nutrition Examination Survey (NHANES).MAIN OUTCOME MEASURE(S)Body weight, height, and calculated body mass index were evaluated using analysis of variance, linear regression, and nonlinear regression to determine the distribution features of size variables and changes associated with time (year), school, and position.RESULTSAmong NESCAC linemen, absolute and relative changes over time in body weight and body mass index exceeded corresponding changes in the NHANES population controls. New England Small College Athletic Conference offensive linemen body weights increased by 37.5% from 1956 to 2014 (192 to 264 lb [86.4 to 118.8 kg]), compared with a 12% increase (164 to 184 lb [73.8 to 82.8 kg]) since 1961 in the NHANES population controls. Body mass index changed in parallel with body weight and exceeded 35 kg/m(2) in more than 30% of contemporary NESCAC offensive linemen. Among skill players in the NESCAC group, time-related changes in body size characteristics generally paralleled those in the NHANES controls.CONCLUSIONSHigh body weight and body mass indices were evident in offensive linemen, even among those in Division III football programs with no athletic scholarships. These characteristics may be associated with adverse cardiovascular and metabolic outcomes. We need approaches to encourage risk modification in the postfootball lifestyles of these individuals.

AIMS:The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo.METHODS:The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers.RESULTS:Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control.CONCLUSION:Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance.

AIMSThe regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has compelled consideration of alternative inhibitors.METHODSThe biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (RAUC ) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor.RESULTSMean (± SE) RAUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). RAUC values were not significantly related to inhibitor dosage or to duration of inhibitor pre-exposure prior to administration of MDZ.CONCLUSIONSRitonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with ketoconazole or ritonavir, and have other significant disadvantages as well.

Clinical Pharmacology in Drug DevelopmentVolume 4, Issue 3 p. 161-162 Editorial Regression and Correlation Jerold S. Harmatz, Jerold S. Harmatz Tufts University School of Medicine, Boston, MA, 02111 USASearch for more papers by this authorDavid J. Greenblatt, David J. Greenblatt Tufts University School of Medicine, Boston, MA, 02111 USASearch for more papers by this author Jerold S. Harmatz, Jerold S. Harmatz Tufts University School of Medicine, Boston, MA, 02111 USASearch for more papers by this authorDavid J. Greenblatt, David J. Greenblatt Tufts University School of Medicine, Boston, MA, 02111 USASearch for more papers by this author First published: 20 May 2015 https://doi.org/10.1002/cpdd.200Citations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume4, Issue3May/June 2015Pages 161-162 RelatedInformation