Predicting Ambulatory Capacity in Parkinson's Disease to Analyze Progression, Biomarkers, and Trial Design.

BACKGROUND: In Parkinson's disease (PD), gait and balance is impaired, relatively resistant to available treatment and associated with falls and disability. Predictive models of ambulatory progression could enhance understanding of gait/balance disturbances and aid in trial design. OBJECTIVES: To predict trajectories of ambulatory abilities from baseline clinical data in early PD, relate trajectories to clinical milestones, compare biomarkers, and evaluate trajectories for enrichment of clinical trials. METHODS: Data from two multicenter, longitudinal, observational studies were used for model training (Tracking Parkinson's, n = 1598) and external testing (Parkinson's Progression Markers Initiative, n = 407). Models were trained and validated to predict individuals as having a "Progressive" or "Stable" trajectory based on changes of ambulatory capacity scores from the Movement Disorders Society Unified Parkinson's Disease Rating Scale parts II and III. Survival analyses compared time-to-clinical milestones and trial outcomes between predicted trajectories. RESULTS: On external evaluation, a support vector machine model predicted Progressive trajectories using baseline clinical data with an accuracy, weighted-F1 (proportionally weighted harmonic mean of precision and sensitivity), and sensitivity/specificity of 0.735, 0.799, and 0.688/0.739, respectively. Over 4 years, the predicted Progressive trajectory was more likely to experience impaired balance, loss of independence, impaired function and cognition. Baseline dopamine transporter imaging and select biomarkers of neurodegeneration were significantly different between predicted trajectory groups. For an 18-month, randomized (1:1) clinical trial, sample size savings up to 30% were possible when enrollment was enriched for the Progressive trajectory versus no enrichment. CONCLUSIONS: It is possible to predict ambulatory abilities from clinical data that are associated with meaningful outcomes in people with early PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Re-Analysis of the STEADY-PD II Trial-Evidence for Slowing the Progression of Parkinson's Disease.

BACKGROUND: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. OBJECTIVES: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined. METHODS: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. RESULTS: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. CONCLUSIONS: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial-suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression. © 2021 International Parkinson and Movement Disorder Society.

Intrahepatic Viral Kinetics During Direct-Acting Antivirals for Hepatitis C in Human Immunodeficiency Virus Coinfection: The AIDS Clinical Trials Group A5335S Substudy.

BACKGROUND: Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection. METHODS: We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S. RESULTS: Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4. CONCLUSIONS: We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.

Raltegravir pharmacokinetics before and during treatment with ombitasvir, paritaprevir/ritonavir plus dasabuvir in adults with human immunodeficiency virus-1 and hepatitis C virus coinfection: AIDS Clinical Trials Group sub-study A5334s.

AIMS: AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight-based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized. METHODS: Adults living with HIV/HCV coinfection receiving steady-state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV. RESULTS: Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration-time curve of raltegravir with vs without HCV therapy were 0.68 (0.38-1.19) and 0.82 (0.58-1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration-time curve values by 41-82% and 4-73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV. CONCLUSIONS: The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide.

Race/Ethnicity and Protease Inhibitor Use Influence Plasma Tenofovir Exposure in Adults Living with HIV-1 in AIDS Clinical Trials Group Study A5202.

AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 2.87 h-1, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.

Multiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202.

BACKGROUND: High-throughput approaches are increasingly being used to identify genetic associations across multiple phenotypes simultaneously. Here, we describe a pilot analysis that considered multiple on-treatment laboratory phenotypes from antiretroviral therapy-naive patients who were randomized to initiate antiretroviral regimens in a prospective clinical trial, AIDS Clinical Trials Group protocol A5202. PARTICIPANTS AND METHODS: From among 5 9545 294 polymorphisms imputed genome-wide, we analyzed 2544, including 2124 annotated in the PharmGKB, and 420 previously associated with traits in the GWAS Catalog. We derived 774 phenotypes on the basis of context from six variables: plasma atazanavir (ATV) pharmacokinetics, plasma efavirenz (EFV) pharmacokinetics, change in the CD4+ T-cell count, HIV-1 RNA suppression, fasting low-density lipoprotein-cholesterol, and fasting triglycerides. Permutation testing assessed the likelihood of associations being by chance alone. Pleiotropy was assessed for polymorphisms with the lowest P-values. RESULTS: This analysis included 1181 patients. At P less than 1.5×10, most associations were not by chance alone. Polymorphisms with the lowest P-values for EFV pharmacokinetics (CYPB26 rs3745274), low-density lipoprotein -cholesterol (APOE rs7412), and triglyceride (APOA5 rs651821) phenotypes had been associated previously with those traits in previous studies. The association between triglycerides and rs651821 was present with ATV-containing regimens, but not with EFV-containing regimens. Polymorphisms with the lowest P-values for ATV pharmacokinetics, CD4 T-cell count, and HIV-1 RNA phenotypes had not been reported previously to be associated with that trait. CONCLUSION: Using data from a prospective HIV clinical trial, we identified expected genetic associations, potentially novel associations, and at least one context-dependent association. This study supports high-throughput strategies that simultaneously explore multiple phenotypes from clinical trials' datasets for genetic associations.

Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques.

The liver is crucial to pharmacology, yet substantial knowledge gaps exist in the understanding of its basic pharmacologic processes. An improved understanding for humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats by using samples collected by fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical resection. Thirteen Sprague-Dawley rats were evaluated, nine of which received paritaprevir/ritonavir at 30/20 mg/kg of body weight by oral gavage daily for 4 or 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3, or 5 passes (FNA1, FNA3, and FNA5); via CNB (16G needle); and via surgical resection. Drug concentrations in plasma were also assessed. Analyses included noncompartmental pharmacokinetic analysis and use of Bland-Altman techniques. All liver tissue samples had higher paritaprevir and ritonavir concentrations than those in plasma. Resected samples, considered the benchmark measure, resulted in estimations of the highest values for the pharmacokinetic parameters of exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between tissue resection and CNB, with 15% bias, followed by FNA3 and FNA5, with 18% bias, and FNA1 and FNA3, with a 22% bias for paritaprevir. Paritaprevir and ritonavir are highly concentrated in rat liver. Further research is needed to validate FNA sampling for humans, with the possible derivation and application of correction factors for drug concentration measurements.

Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s.

Background: It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. Methods: We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n = 134) versus abacavir ( n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Results: Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r = -0.22, P = 0.028) and week 48 ( r = -0.26, P = 0.010), but not at week 96 ( r = -0.14, P = 0.18). Conclusions: Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.

Efavirenz Therapeutic Range in HIV-1 Treatment-Naive Participants.

BACKGROUND: Efavirenz is currently suggested as an alternative to recommended antiretroviral (ARV) regimens by the Department of Health and Human Services for the treatment of HIV-1 in ARV-naive patients. A mid-dosing interval therapeutic range between 1000 and 4000 ng/mL for efavirenz has been proposed in the literature, with patients more likely to experience virologic failure below this range and adverse effects above. The current study reports an analysis of virologic outcome between those above, below, or within the reported efavirenz therapeutic range (1000-4000 ng/mL) and within subgroups. METHODS: This analysis examined efavirenz plasma concentrations obtained from participants enrolled in AIDS Clinical Trials Group Study A5202. This investigation divided subjects into those who experienced virologic failure and those who did not. These subjects were further separated to investigate those who had "high," "within," or "low" plasma concentrations, based on the therapeutic range. The association between virologic failure and plasma concentration was statistically examined in addition to the variables: race/ethnicity, sex, assigned nucleos(t)ide reverse transcriptase inhibitor backbone, age at study entry, history of intravenous drug use, weight, and screening HIV-1 RNA stratification level. RESULTS: In univariate analyses, a statistically significant difference was found when comparing the efavirenz concentration groups, (22 failures among the "low" concentration group [19%], 65 failures among the "within" concentration group [12%], and 11 failures among the "high" concentration group [9%]) when evaluating virologic failure as an outcome (P = 0.04). In addition, the proportion of participants with virologic failure differed across race/ethnicity groups (P = 0.03) with black non-Hispanic participants observed to have the highest rate (17%). Efavirenz concentration group, race/ethnicity, age, weight, and the interaction between efavirenz concentration group and weight were found to be significantly associated with virologic failure in multivariable logistic regression analysis. CONCLUSIONS: The proposed efavirenz therapeutic range, combined with the impact of a patient's weight, is associated with virologic failure in HIV-infected ARV-naive individuals in the United States. Additional analysis is recommended to determine the most appropriate concentration value that defines the lower limit of the efavirenz therapeutic range.

Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation.

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV-infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX-treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype (GT) 1-infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1-infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies.

A review of disease progression models of Parkinson's disease and applications in clinical trials.

Quantitative disease progression models for neurodegenerative disorders are gaining recognition as important tools for drug development and evaluation. In Parkinson's disease (PD), several models have described longitudinal changes in the Unified Parkinson's Disease Rating Scale (UPDRS), one of the most utilized outcome measures for PD trials assessing disease progression. We conducted a literature review to examine the methods and applications of quantitative disease progression modeling for PD using a combination of key words including "Parkinson disease," "progression," and "model." For this review, we focused on models of PD progression quantifying changes in the total UPDRS scores against time. Four different models reporting equations and parameters have been published using linear and nonlinear functions. The reasons for constructing disease progression models of PD thus far have been to quantify disease trajectories of PD patients in active and inactive treatment arms of clinical trials, to quantify and discern symptomatic and disease-modifying treatment effects, and to demonstrate how model-based methods may be used to design clinical trials. The historical lack of efficiency of PD clinical trials begs for model-based simulations in planning for studies that result in more informative conclusions, particularly around disease modification. © 2016 International Parkinson and Movement Disorder Society.

Genomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202. METHODS: Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms. RESULTS: Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10). CONCLUSION: Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.

Pharmacokinetics of ε-Aminocaproic Acid in Neonates Undergoing Cardiac Surgery with Cardiopulmonary Bypass.

BACKGROUND: Antifibrinolytic medications such as ε-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. METHODS: Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). RESULTS: Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h × (WT/70). Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg · kg · h, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. CONCLUSIONS: EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults.

Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine.

BACKGROUND: We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. METHODS: We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1-infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII). RESULTS: Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex. CONCLUSIONS: This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential. CLINICAL TRIALS REGISTRATION: NCT00118898.

Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.

BACKGROUND: Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. METHODS: Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available. RESULTS: Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance. CONCLUSION: Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.

Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202.

OBJECTIVES: It is uncertain whether HIV-1 antiretroviral exposure and clinical response varies between males and females or different race/ethnic groups. We describe ritonavir-enhanced atazanavir pharmacokinetics in relation to virological failure, safety and tolerability in treatment-naive individuals to investigate potential differences. METHODS: Plasma samples were collected from participants in AIDS Clinical Trials Group Study A5202 for measurement of antiretroviral concentrations. Individual estimates of apparent oral clearance of atazanavir (L/h) were calculated from a one-compartment model and divided into tertiles as slow (<7), middle (7 to <9; reference group) and fast (≥9). Associations between atazanavir clearance and clinical outcomes were estimated with a hazard ratio (HR) from Cox proportional hazards models. Interactions between atazanavir clearance and sex, race/ethnicity and NRTIs were investigated for each of the outcomes. RESULTS: Among 786 participants, average atazanavir clearance was slower in females (n = 131) than males (n = 655). Atazanavir clearance was associated with time to virological failure (P = 0.053) and this relationship differed significantly by sex (P = 0.003). Females in the fast atazanavir clearance group had shorter time to virological failure (HR 3.49; 95% CI 1.24-9.84) compared with the middle (reference) atazanavir clearance group. Among males, the slow atazanavir clearance group had a higher risk of virological failure (HR 2.10; 95% CI 1.16-3.77). CONCLUSIONS: Atazanavir clearance differed by sex. Females with fast clearance and males with slow clearance had increased risk of virological failure.

Oral ketamine for children with chronic pain: a pilot phase 1 study.

OBJECTIVE: To assess whether oral ketamine is safe at higher dosages for sedating children and whether it may be an option for the control of chronic pain in children. STUDY DESIGN: A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.25-1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment. RESULTS: Two participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, 2 with complete resolution of pain, lasting >4 weeks off ketamine treatment. CONCLUSION: Oral ketamine at dosages of 0.25-1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain.

Developing better digital health measures of Parkinson's disease using free living data and a crowdsourced data analysis challenge.

One of the promising opportunities of digital health is its potential to lead to more holistic understandings of diseases by interacting with the daily life of patients and through the collection of large amounts of real-world data. Validating and benchmarking indicators of disease severity in the home setting is difficult, however, given the large number of confounders present in the real world and the challenges in collecting ground truth data in the home. Here we leverage two datasets collected from patients with Parkinson's disease, which couples continuous wrist-worn accelerometer data with frequent symptom reports in the home setting, to develop digital biomarkers of symptom severity. Using these data, we performed a public benchmarking challenge in which participants were asked to build measures of severity across 3 symptoms (on/off medication, dyskinesia, and tremor). 42 teams participated and performance was improved over baseline models for each subchallenge. Additional ensemble modeling across submissions further improved performance, and the top models validated in a subset of patients whose symptoms were observed and rated by trained clinicians.

Pharmacologic approaches to the treatment of Huntington's disease.

Huntington's disease (HD) is an inherited, progressive neurodegenerative disorder characterized by chorea, cognitive impairment, and behavioral disturbances. Despite advances in diagnosis and improved understanding of HD, treatment remains difficult due to challenging symptoms and a paucity of approved therapeutic interventions. Nonpharmacologic and pharmacologic strategies have been evaluated; regarding the latter, over 80 agents of various classes have been investigated in clinical trials or examined in case reports. Symptomatic treatment, however, is generally confined to antidopaminergic agents for motor dysfunction and antidepressants for mood disorders, while treatment for cognitive dysfunction remains vacant. Several different mechanisms to modify symptoms and disease progression have been targeted in clinical trials. This article reviews some of the more common pharmacologic treatments used for HD, discusses data regarding suboptimal agents that have been tested, and surveys treatments under investigation.

Prevalence and Incidence of Nonmotor Symptoms in Individuals with and Without Parkinson's Disease.

Background: The prevalence ratio (PR) and incidence rate ratio (IRR) of nonmotor symptoms (NMS) were calculated for early Parkinson's disease (PD) versus non-PD from 2 observational studies. Methods: NMS were assessed through the self-reported Non-Motor Symptom Questionnaire in the online Fox Insight study and through self- and clinician-rated scales in the Parkinson's Progression Marker Initiative (PPMI) study. Age- and sex-adjusted/matched PR and IRR were estimated for each NMS by PD status using Poisson regression. Results: Most NMS occurred more frequently in PD. Among 15,194 Fox Insight participants, sexual dysfunction had the largest adjusted PR (12.4 [95% CI, 6.9-22.2]) and dysgeusia/hyposmia had the largest adjusted IRR over a 2-year median follow-up (17.0 [95% CI, 7.8-37.1]). Among 607 PPMI participants, anosmia had the largest PR (16.6 [95% CI, 6.1-44.8]). During the 7-year median follow-up, hallucinations had the largest IRR (13.5 [95% CI, 6.3-28.8]). Conclusion: Although many NMS are more common in early PD than in non-PD, their occurrence may differ with time (hallucinations) or data collection methods (sexual dysfunction).