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With more potent drug candidates being developed, the incidence of target-mediated drug disposition (TMDD) in small-molecule compounds has significantly increased in the past decade. Moreover, TMDD appears to apply to some small-molecule compound classes. The main purpose of the current review is to increase the awareness of TMDD in a series of small-molecule inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) using ABT-384, SPI-62, MK-0916, BMS-823778, and BI-187004 as case examples. Although developed independently by different pharmaceutical companies, these HSD-1 inhibitors demonstrated strikingly similar nonlinear pharmacokinetic behaviors when wide dose ranges were evaluated in first-in-human (FIH) single ascending dose (SAD) and multiple ascending dose (MAD) studies. Recognizing TMDD in small-molecule compounds is important, as the information can be leveraged to select the appropriate dose regimen, improve clinical trial design, as well as predict pharmacological target occupancy. In this review, we summarize the general pharmacokinetic features that facilitate the recognition of small-molecule TMDD, provide case examples of specific HSD-1 inhibitors, highlight the importance of recognizing TMDD of small-molecule compounds during clinical development, and comment on the importance of utilizing pharmacometric modeling to facilitate the quantitative understanding of small-molecule compounds exhibiting TMDD., (© 2022, The American College of Clinical Pharmacology.)

Background: Emergency departments (ED) interface with large numbers of patients that are often missed by conventional HIV testing approaches. ED-based HIV self-testing (HIVST) is an innovative engagement approach which has potential for testing gains among populations that have failed to be reached. This systematic review and meta-analysis evaluated acceptability and uptake of HIVST, as compared to standard provider-delivered testing approaches, among patients seeking care in ED settings., Methods: Six electronic databases were systematically searched (Dates: January 1990-May 2021). Reports with data on HIVST acceptability and/or testing uptake in ED settings were included. Two reviewers identified eligible records (κ= 0.84); quality was assessed using formalized criteria. Acceptability and testing uptake metrics were summarized, and pooled estimates were calculated using random-effects models with assessments of heterogeneity., Results: Of 5773 records identified, seven met inclusion criteria. The cumulative sample was 1942 subjects, drawn from three randomized control trials (RCTs) and four cross-sectional studies. Four reports assessed HIVST acceptability. Pooled acceptability of self-testing was 92.6% (95% confidence interval [CI]: 88.0%-97.1%). Data from two RCTs demonstrated that HIVST significantly increased testing uptake as compared to standard programs (risk ratio [RR] = 4.41, 95% CI: 1.95-10.10, I 2  = 25.8%). Overall, the quality of evidence was low (42.9%) or very low (42.9%), with one report of moderate quality (14.2%)., Conclusions: Available data indicate that HIVST may be acceptable and may increase testing among patients seeking emergency care, suggesting that expanding ED-based HIVST programs could enhance HIV diagnosis. However, given the limitations of the reports, additional research is needed to better inform the evidence base., (© 2021 Society for Academic Emergency Medicine.)

SPI-62 is a selective and potent small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). SPI-62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose-dependent volume of distribution, nonlinear PK following the first dose, and dose-proportional PK at steady state, as well as unusually high accumulation ratios at low doses. The most likely explanation for the observed nonlinearity of SPI-62 is the saturable binding of SPI-62 to its pharmacological target HSD-1, a phenomenon known as target-mediated drug disposition (TMDD). Because of the nonlinear and complex PK of SPI-62, the relationship among SPI-62 dose, exposure, and response is no longer intuitive and consequently dose selection can be challenging. To facilitate dose selection and clinical trial design, in the current study population PK analysis was performed to characterize SPI-62 dose-exposure relationship in humans quantitatively. SPI-62 PK was best characterized by a 2-compartment TMDD model with 3 transit absorption compartments. The model was successfully established to explain the substantial and unusual nonlinear PK of SPI-62 in humans, and it provided adequate fitting for both single- and multiple-dose data. Our modeling work has provided a strong foundation for dose selection in future SPI-62 clinical trials., (© 2021 Sparrow Pharmaceuticals, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objective: Admission to the chest pain observation unit (CPOU) may be an advantageous time for patients to consider heart-healthy lifestyle changes while undergoing diagnostic evaluation to rule out myocardial ischemia. The aim of this pragmatic trial was to assess the effectiveness of a multiple risk factor intervention in changing CPOU patients' health beliefs and readiness to change health behaviors. A secondary aim was to obtain preliminary estimates of the intervention's effect on diet, physical activity, and smoking., Methods: We conducted a pilot randomized controlled trial of a moderate-intensity counseling intervention that aimed to build motivation to change and problem-solving skills in 140 adult patients with at least one modifiable cardiovascular risk factor (CRF) who were admitted to the CPOU of an academic emergency department (ED) with symptoms of possible acute coronary syndrome. Study patients were randomly assigned to full counseling (face-to-face cardiovascular risk assessment and personalized counseling on nutrition, physical activity, and smoking cessation in the ED, plus two telephone follow-up sessions) or minimal counseling (brief instruction [<5 minutes] on benefits of modifying cardiovascular risk factors) by a cardiac rehabilitation specialist. We measured Health Belief Model constructs for ischemic heart disease, stage of change, and self-reported CRF-related behaviors (diet, exercise, and smoking) during 6-month follow-up using previously validated measures. We used linear mixed models and logistic regression (with generalized estimating equations) to compare continuous and dichotomous behavioral outcomes across treatment arms, respectively., Results: Approximately 20% more patients in the full counseling arm reported having received counseling on diet and physical activity during CPOU admission, compared to the minimal counseling arm; a similar proportion of patients in both counseling arms reported having received advice or assistance in quitting smoking. There were no significant differences between treatment arms for any cardiovascular health beliefs, readiness to change, or CRF-related behaviors during longitudinal follow-up. In secondary analyses in both treatment arms combined, however, patients showed significant differences between follow-up and baseline measurements: increases in the perceived benefits of improving CRF-related behaviors (27.7 vs. 26.6 on a scale from 7 to 35, p = 0.0001) and increased readiness to change dietary behavior and physical activity during follow-up-intake of saturated fat (83% vs. 49%), readiness to change fruit and vegetable consumption (83% vs 56%), and readiness to perform regular exercise (34% vs. 14%) at 6 months and baseline, respectively (p < 0.0001 for all comparisons in both treatment arms combined)., Conclusions: A multiple risk factor intervention that focused on increasing motivation to change and problem-solving skills did not significantly improve behavioral outcomes, compared to minimal counseling. Patients admitted to the CPOU demonstrated sustained changes in several cardiovascular health beliefs and risk-related behaviors during follow-up; this provides further evidence that the CPOU visit is a "teachable moment" for cardiovascular risk reduction. Future studies should evaluate the effectiveness of ED-initiated counseling interventions to engage patients in changing cardiovascular risk behaviors, in coordination with primary care., (© 2017 by the Society for Academic Emergency Medicine.)

ABT-384 is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). The pharmacokinetics of ABT-384 was evaluated in healthy volunteers in single-dose (1, 8, 20, 50, 120 and 240 mg) and multiple-dose studies (1, 2, 4, 8, 20, 30 and 100 mg once daily). Less than dose-proportional pharmacokinetics of ABT-384 was observed when ABT-384 was administered at single doses lower than 8 mg. This nonlinear phenomenon disappeared after repeated doses. The dose-normalized plasma concentration-time curves superposed across all dose groups on day 7, but not on day 1. This phenomenon cannot be explained by the half-life of ABT-384. Based on available data, the nonlinearity is likely due to binding of ABT-384 to a high-affinity-low-capacity site, such that this interaction was reflected in ABT-384 pharmacokinetics. To characterize the pharmacokinetics of ABT-384, a population pharmacokinetic model for ABT-384 was constructed. The model provided reasonable fitting for both single- and multiple-dose data. Further investigation is warranted to evaluate the disposition of ABT-384 at low doses using a larger number of subjects. The constructed model would be useful in predicting ABT-384 concentrations at different doses and guiding the selection of dosing regimens in further clinical trials., (Copyright © 2014 John Wiley & Sons, Ltd.)

ABT-384 is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1), the enzyme that regenerates cortisol in several tissues. Two clinical studies of ABT-384 were undertaken to assess its safety, pharmacokinetics, target engagement, and pharmacologic effects in healthy subjects. Single doses from 1 to 240 mg, and multiple doses from 1 to 100 mg once daily for 7-14 days, were administered to healthy adults. Multiple doses from 10 to 100 mg once daily for 21 days were administered to elderly subjects. A total of 103 subjects received at least 1 dose of ABT-384. A maximum-tolerated dose was not defined in either study. The pharmacokinetic profiles of ABT-384 and its active metabolite support once daily dosing. Analysis of urine cortisol metabolites demonstrated full hepatic HSD-1 inhibition with regimens from 1 mg daily, and confirmed in vitro target selectivity. Pharmacologic effects included increases of adrenocorticotrophic hormone levels, cortisol production and androgen and estradiol levels. ABT-384 has a wide therapeutic index relative to full hepatic target engagement which is relevant for indications such as diabetes and metabolic syndrome. Its therapeutic index for other potential indications such as Alzheimer's disease remains to be established., (© The Author(s) 2013.)

Objectives: The focus on acute care, time pressure, and lack of resources hamper the delivery of smoking cessation interventions in the emergency department (ED). The aim of this study was to 1) determine the effect of an emergency nurse-initiated intervention on delivery of smoking cessation counseling based on the 5As framework (ask-advise-assess-assist-arrange) and 2) assess ED nurses' and physicians' perceptions of smoking cessation counseling., Methods: The authors conducted a pre-post trial in 789 adult smokers (five or more cigarettes/day) who presented to two EDs. The intervention focused on improving delivery of the 5As by ED nurses and physicians and included face-to-face training and an online tutorial, use of a charting/reminder tool, fax referral of motivated smokers to the state tobacco quitline for proactive telephone counseling, and group feedback to ED staff. To assess ED performance of cessation counseling, a telephone interview of subjects was conducted shortly after the ED visit. Nurses' and physicians' self-efficacy, role satisfaction, and attitudes toward smoking cessation counseling were assessed by survey. Multivariable logistic regression was used to assess the effect of the intervention on performance of the 5As, while adjusting for key covariates., Results: Of 650 smokers who completed the post-ED interview, a greater proportion had been asked about smoking by an ED nurse (68% vs. 53%, adjusted odds ratio [OR] = 2.0, 95% confidence interval [CI] = 1.3 to 2.9), assessed for willingness to quit (31% vs. 9%, adjusted OR= 4.9, 95% CI = 2.9 to 7.9), and assisted in quitting (23% vs. 6%, adjusted OR = 5.1, 95% CI = 2.7 to 9.5) and had arrangements for follow-up cessation counseling (7% vs. 1%, adjusted OR = 7.1, 95% CI = 2.3 to 21) during the intervention compared to the baseline period. A similar increase was observed for emergency physicians (EPs). ED nurses' self-efficacy and role satisfaction in cessation counseling significantly improved following the intervention; however, there was no change in "pros" and "cons" attitudes toward smoking cessation in either ED nurses or physicians., Conclusions: Emergency department nurses and physicians can effectively deliver smoking cessation counseling to smokers in a time-efficient manner. This trial also provides empirical support for expert recommendations that call for nursing staff to play a larger role in delivering public health interventions in the ED., (© 2012 by the Society for Academic Emergency Medicine.)

Objectives: Even after acute coronary syndrome (ACS) is ruled out, observational studies have suggested that many patients with nonspecific chest pain have a high burden of cardiovascular risk factors (CRFs) and are at increased long-term risk of ischemic heart disease (IHD)-related mortality. The aim of this study was to evaluate the premise that evaluation in an observation unit for symptoms of possible ACS is a "teachable moment" with regard to modification of CRFs., Methods: The authors conducted a baseline face-to-face interview and a 3-month telephone interview of 83 adult patients with at least one modifiable CRF who presented with symptoms of possible ACS to an academic medical center. Existing questionnaires were adapted to measure Health Belief Model (HBM) constructs for IHD. Stage of change and self-reported CRF-related behaviors (diet, exercise, and smoking) were assessed using previously validated measures. The paired t-test or signed rank test was used to compare baseline and 3-month measures of health behavior within the analysis sample., Results: Of the 83 study patients, 45 and 40% reported having received clinician advice regarding diet and physical activity during the observation unit encounter, respectively; 69% of current smokers received advice to quit smoking. Patients reported lower susceptibility to IHD (13.3 vs. 14.0, p = 0.06) and greater perceived benefit of healthy lifestyles (27.5 vs. 26.4, p = 0.0003) at 3-month follow-up compared to baseline. Patients also reported greater readiness to change and improved self-reported behaviors at follow-up (vs. baseline): decreased intake of saturated fat (10.1% vs. 10.5% of total calories, p = 0.005), increased fruit and vegetable intake (4.0 servings/day vs. 3.6 servings/day, p = 0.01), and fewer cigarettes (13 vs. 18, p = 0.002)., Conclusions: Observed changes in IHD health beliefs and CRF-related behaviors during follow-up support the idea that observation unit admission is a teachable moment. Patients with modifiable risk factors may benefit from systematic interventions to deliver CRF-related counseling during observation unit evaluation.

Pharmacogenomic (PGx) research on the absorption, distribution, metabolism, and excretion (ADME) properties of drugs has begun to have impact for both drug development and utilization. To provide a cross-industry perspective on the utility of ADME PGx, the Pharmaceutical Research and Manufacturers of America (PhRMA) conducted a survey of major pharmaceutical companies on their PGx practices and applications during 2003-2005. This white paper summarizes and interprets the results of the survey, highlights the contributions and applications of PGx by industrial scientists as reflected by original research publications, and discusses changes in drug labels that improve drug utilization by inclusion of PGx information. In addition, the paper includes a brief review on the clinically relevant genetic variants of drug-metabolizing enzymes and transporters most relevant to the pharmaceutical industry.

The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open-label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half-life by 77% (P<.05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide-mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.

In the CYP3A5 gene, the A>G (*3) and G>A (*6) polymorphisms result in severely decreased expression of CYP3A5 enzyme relative to a normal functional allele (*1). We sought to determine if the CYP3A5 genetic polymorphisms were associated with level of blood pressure (BP), risk of hypertension (HTN), and the antihypertensive response to verapamil. A total of 676 normotensive and hypertensive participants (mean age 49+/-8.2 years) from the Hypertension Genes study and 722 patients (mean age 66+/-9 years) from the International Verapamil/Trandolapril Study Genetic Substudy (INVEST-GENES) were genotyped for CYP3A5 to test for associations with BP, HTN, and in the latter cohort, antihypertensive response to verapamil. CYP3A5 haplotypes were determined using PHASE 2, with any allele containing either (*3) or (*6) designated as non functional. In the HTN genes population, there were no significant differences based on the number of functional CYP3A5 alleles, in systolic blood pressure (SBP) or diastolic blood pressure (DBP) among the normotensive whites or blacks (all P> or =0.70) or in allele frequency between normotensives and hypertensives. In INVEST-GENES, when controlled for baseline BP, race, age, and gender, untreated BP in carriers versus non carriers of a CYP3A5 functional allele was 158.2+/-13.7 and 154.8+/-13.7 (P=0.061), respectively. CYP3A5 functional allele status was marginally associated with the SBP response to verapamil in blacks (P=0.075) and Hispanics (P=0.056), but not in whites (P=0.40), with the effect being largely driven by higher SBP in the carriers of two functional alleles. There was no association with DBP response and CYP3A5 allele status. CYP3A5 genotype does not contribute importantly to BP or risk of HTN, but may influence response to calcium channel blockers in populations in which carrier status of two functional alleles is common.

Objective: Our objective was to learn whether genetic polymorphisms of metabolic enzymes or transport proteins provide a mechanistic understanding of the in vivo disposition of atrasentan, a selective endothelin A receptor antagonist., Methods: Atrasentan uptake was measured in HeLa cells transfected to express major alleles of organic anion transporting polypeptide 1B1 (OATP1B1). The results were used to classify individuals as extensive, intermediate, or poor OATP1B1 transporters according to their SLCO1B1 genotypes. Analysis of covariance including genotype, study, age, weight, sex, and ethnicity was used to identify factors influencing atrasentan single-dose (n = 44) and steady-state (n = 38) pharmacokinetic parameters. Genotypes for cytochrome P450 3A5, uridine diphosphate-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B15, adenosine triphosphate-binding cassette subfamily B (ABCB) 1, solute carrier organic anion transporter (SLCO) 1B1, and solute carrier family 22 (SLC22) A2 were each assessed., Results: Single-dose atrasentan exposure (P = .0244), steady-state atrasentan exposure (P = .0108), and maximum postdose plasma concentration (P = .0002) were associated with OATP1B1 activity classified by SLCO1B1 genotype. No other tested genotypes were observed to be associated with both single-dose and steady-state atrasentan pharmacokinetics., Conclusions: OATP1B1 is a meaningful factor for atrasentan disposition. Individuals may be classified as having extensive, intermediate, or poor OATP1B1 transport phenotypes according to SLCO1B1 genotypes. Increased exposures of OATP1B1 substrates might be expected in individuals who have the poor transporter phenotype or are treated with an OATP1B1 inhibitor.

Background: The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically expressed as a result of genetic variants that do not encode functional protein. Because of overlapping substrate specificity with CYP3A4 and the multidrug efflux pump P-glycoprotein, the importance of CYP3A5 genetic polymorphism for pharmacokinetics is controversial., Objective: Our objective was to determine whether genetic polymorphisms in CYP3A5 or MDR-1 (which encodes P-glycoprotein) influence the drug levels of ABT-773, a ketolide antibiotic that is a substrate for both CYP3A and P-glycoprotein., Methods: Healthy volunteers given 3 different oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1 polymorphisms. Individuals were categorized as CYP3A5-positive if they carried at least 1 functional CYP3A5*1 allele and as CYP3A5-negative if they did not. Area under the plasma concentration-time curves (AUCs) from 0 to 6 hours (AUC(t)) and maximum postdose plasma concentration (C(max)) after a single dose and on day 5 of a twice-daily regimen were calculated and correlated with genotypes., Results: ABT-773 AUC(t) and C(max) were, on average, higher in CYP3A5-negative subjects given 450 mg ABT-773 (n = 9) than in CYP3A5-positive subjects with identical doses (n = 8). The relationship for AUC(t) was statistically significant both after a single dose (geometric mean and 95% confidence interval [CI], 5.0 microg.h/mL [3.9-6.4 microg.h/mL] versus 2.8 microg.h/mL [1.8-4.3 microg.h/mL]; P =.03) and on the fifth day of twice-daily dosing (12.4 microg.h/mL [8.7-17.6 microg.h/mL] versus 7.4 microg.h/mL [5.5-9.8 microg.h/mL], P =.04). The relationship for C(max) was statistically significant after a single dose (1220 microg/mL [867-1167 microg/mL] versus 727 microg/mL [506-1044 microg/mL], P =.04) and showed a trend in the same direction on the fifth day of twice-daily dosing (2566 microg/mL [1813-3631 microg/mL] versus 1621 microg/mL [1122-2343 microg/mL], P =.07). In contrast, AUC(t) and C(max) were not significantly different between CYP3A5-positive and CYP3A5-negative individuals given 150 mg or 300 mg ABT-773. ABT-773 plasma levels did not trend with MDR-1 genotypes., Conclusions: These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose-dependent.

Phentermine and fenfluramine are widely used in the treatment of obesity. Despite the fact that primary pulmonary hypertension and mitral valve insufficiency have been associated with fenfluramine use, many of these patients need medication to achieve weight loss. Small degrees of weight loss have been shown to significantly improve obesity-related medical conditions such as hypertension, hypercholesterolemia, and noninsulin-dependent diabetes mellitus. Current practice is to give phentermine and fenfluramine in the morning and afternoon. Doses for phentermine have ranged from 15 to 37.5 mg and for fenfluramine from 20 to 120 mg per day. We report five cases of severely obese women with medical complications who were treated with phentermine 8 mg twice per day (at 1:00 p.m. and 4:00 p.m.) and fenfluramine 20 mg per day (at 4:00 p.m.). Because many obese patients skip breakfast and eat more in the afternoon and evening, medication was dosed in order to cover these high-risk eating periods. Overall, these patients lost a mean of 22.4% of their initial weight (range 18.6% to 32.8%) over an average of 8.4 months (range 3.5 to 16 months). These cases suggest that short-term weight loss can be achieved with a low dose of fenfluramine when both medications are given in the afternoon to better target the eating patterns of obese subjects.

Immunoblastic sarcoma is a malignancy of transformed lymphocytes with a high association of occurrence in patients with immune disorders. The youngest previously reported case occurred in a 6-year-old child with immunoblastic lymphadenopathy. The authors report the finding of immunoblastic sarcoma of B-cells in a previously healthy 24-month-old boy. This represents the youngest reported patient with this lymphoma.