Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial.

Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04310579.

Effect of Oral Ranitidine on Urinary Excretion of N-Nitrosodimethylamine (NDMA): A Randomized Clinical Trial.

Importance: In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption. Objective: To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020. Interventions: Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. Main Outcome and Measure: Twenty-four-hour urinary excretion of NDMA. Results: Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported. Conclusions and Relevance: In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population. Trial Registration: ClinicalTrials.gov Identifier: NCT04397445.

Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk.

INTRODUCTION: The electrocardiographic index Tpeak-Tend has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation. METHODS AND RESULTS: We assessed whether quinidine-induced Tpeak-Tend prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38 ± 10 vs. 28 ± 9 ms/µg/ml, p=0.02), but there was no difference for Tpeak-Tend prolongation (39 ± 13 vs. 32 ± 13 ms/µg/ml, p=0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and Tpeak-Tend prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55 ± 18 vs. 43 ± 19 ms/µg/ml, p=0.14), without changing the lack of sex difference with Tpeak-Tend (61 ± 22 vs. 55 ± 21 ms/µg/ml, p=0.49). CONCLUSIONS: Women do not have a greater quinidine-induced Tpeak-Tend prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation.

Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies.

BACKGROUND & AIMS: Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development. METHODS: We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylated-interferon, ribavirin, and direct-acting antivirals. RESULTS: The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection. CONCLUSIONS: SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children.

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial.

Importance: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl). Objective: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose. Design, Setting, and Participants: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023. Intervention: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference). Main Outcomes and Measures: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics. Results: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes. Conclusions and Relevance: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04764630.

Pharmacodynamic Biomarkers Evidentiary Considerations for Biosimilar Development and Approval.

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from a US Food and Drug Administration (FDA)-approved reference product. The development and approval of biosimilars is critical to enhancing the availability of safe, effective, and affordable treatment options for patients. Utilization of pharmacodynamic (PD) biomarkers can help streamline biosimilar development programs as the current process can be costly and time-consuming. Whereas PD biomarkers have not been prominently used across biosimilar approvals to date, moving forward, there is ample opportunity to increase the use of PD biomarkers in biosimilar development programs in place of comparative clinical studies with efficacy end point(s). This includes utilizing PD biomarkers that were not used as surrogate end points in approval of reference products. This mini-review summarizes how PD biomarkers have been used in biosimilar development programs to date and then discusses evidentiary considerations for PD biomarkers. In addition, study design considerations for clinical pharmacokinetic and PD assessment of proposed biosimilars are discussed. Finally, the FDA's applied regulatory science activities related to PD biomarkers for biosimilars conducted in support of the FDA's Biosimilars Action Plan are reviewed. This included conducting three clinical studies to address information gaps about PD biomarkers for biosimilars and inform general methodological best practices. In summary, enhancing our understanding of key evidentiary considerations and optimal study designs for incorporating PD biomarkers in the evaluation of proposed biosimilars can help bring more treatment options to patients faster.

A Bioanalytical Method for Quantification of N-nitrosodimethylamine (NDMA) in Human Plasma and Urine with Different Meals and following Administration of Ranitidine.

Control of N-nitrosoamine impurities is important for ensuring the safety of drug products. Findings of nitrosamine impurities in some drug products led FDA to develop new guidance providing recommendations for manufacturers towards prevention and detection of nitrosamine impurities in pharmaceutical products. One of these products, ranitidine, also had a published in vivo study, which has since been retracted by its authors, suggesting a potential for in vivo conversion of ranitidine to the probable human carcinogen, N-nitrosodimethylamine (NDMA). FDA subsequently initiated a randomized, double-blind, placebo-controlled, crossover clinical investigation to assess the potential for in vivo conversion of ranitidine to NDMA with different meals. A bioanalytical method toward characterization of NDMA formation was needed as previously published methods did not address potential NDMA formation after biofluid collection. Therefore, a bioanalytical method was developed and validated as per FDA's Bioanalytical Method Validation guidance. An appropriate surrogate matrix for calibration standards and quality control sample preparation for both liquid matrices (human plasma and urine) was optimized to minimize the artifacts of assay measurements and monitor basal NDMA levels. Interconversion potential of ranitidine to NDMA was monitored during method validation by incorporating the appropriate quality control samples. The validated methods for NDMA were linear from 15.6 pg/mL to 2000 pg/mL. Low sample volumes (2 mL for urine and 1 mL for plasma) made this method suitable for clinical study samples and helped to evaluate the influence of ranitidine administration and meal types on urinary excretion of NDMA in human subjects.

Model-Based Approach to Selecting Pegfilgrastim Dose for Pharmacokinetic and Pharmacodynamic Similarity Studies in Biosimilar Development.

This study applied modeling and simulation (M&S) approaches to evaluate the sensitivity of pegfilgrastim pharmacokinetics (PKs) and pharmacodynamics (PDs) to changes in dose amount, and linear or nonlinear clearance (CL) over pegfilgrastim subcutaneous dose of 2-6 mg. A previously published model was adapted to better describe pegfilgrastim PK and PD data in healthy subjects and used in simulation. Nonlinear CL accounts for 98% and 77%, respectively, of the total CL of pegfilgrastim at 2 and 6 mg. The sensitivity analyses showed: (i) PK of 2 and 6 mg doses are similarly sensitive to detect differences for a 5% change in dose; (ii) PK of 2 mg dose is more sensitive to changes in receptor binding affinity, a model parameter for nonlinear CL, and a product quality attribute characterized with orthogonal methods as part of demonstrating analytical similarity between products; (iii) PK of approved 6 mg dose is more sensitive to changes in linear CL, which has not been associated with any specific product quality attributes, and (iv) the PDs are not sensitive to changes in linear or nonlinear CL. Taken together, our analyses support that the approved pegfilgrastim dose of 6 mg is appropriate for detecting differences between a biosimilar and the reference products in pegfilgrastim PK and PD similarity studies. The described M&S approaches can be adopted to support dose selection for biosimilars with nonlinear PK and complex PK-PD interplay.

Informing a Comprehensive Risk Assessment of Infant Drug Exposure From Human Milk: Application of a Physiologically Based Pharmacokinetic Lactation Model for Sotalol.

Characterization of infant drug exposure through human milk is important and underexplored. Because infant plasma concentrations are not frequently collected in clinical lactation studies, modeling and simulation approaches can integrate physiology, available milk concentrations, and pediatric data to inform exposure in breastfeeding infants. A physiologically based pharmacokinetic model was built for sotalol, a renally eliminated drug, to simulate infant drug exposure from human milk. Intravenous and oral adult models were built, optimized, and scaled to an oral pediatric model for a breastfeeding-relevant age group (<2 years). Model simulations captured the data that were put aside for verification. The resulting pediatric model was applied to predict the impacts of sex, infant body size, breastfeeding frequency, age, and maternal dose (240 and 433 mg) on drug exposure during breastfeeding. Simulations suggest a minimal effect of sex or frequency on total sotalol exposure. Infants in the 90th percentile in height and weight have predicted exposures ≈20% higher than infants of the same age in the 10th percentile due to increased milk intake. The simulated infant exposures increase throughout the first 2 weeks of life and are maintained at the highest concentrations in weeks 2-4, with a consistent decrease observed as infants age. Simulations suggest that breastfeeding infants will have plasma concentrations in the lower range observed in infants administered sotalol. With further validation on additional drugs, physiologically based pharmacokinetic modeling approaches could use lactation data to a greater extent and provide comprehensive information to support decisions regarding medication use during breastfeeding.

Pharmacodynamic Biomarkers for Biosimilar Development and Approval: A Workshop Summary.

The US Food and Drug Administration (FDA) Biosimilars Guidance describes how biosimilars may be approved based on clinical pharmacokinetic and pharmacodynamic (PD) biomarker data, without comparative clinical studies with efficacy end points. This type of clinical development program, however, has only been implemented for a small number of FDA-approved biosimilar products over the last decade. To encourage the use of PD biomarkers in biosimilar development and approval, the Duke-Margolis Center for Health Policy collaborated with the FDA to host a two-day virtual public workshop entitled "Pharmacodynamic Biomarkers for Biosimilar Development and Approval" on September 20-21, 2021. The public workshop was a forum for global regulators, biopharmaceutical developers, and academic researchers to discuss the current and future role of PD biomarkers in improving the efficiency of biosimilar development and approval. The workshop objectives included: (i) discuss the current and potential future state of leveraging PD biomarkers for biosimilar development and approval; (ii) summarize the FDA's initiatives to advance biosimilar development; (iii) describe stakeholders' experience with PD biomarkers in biosimilar development; and (iv) explain research efforts to promote broader application of PD biomarkers in biosimilar development. This document summarizes presentations and panel discussions from each session of the two-day September 2021 public workshop covering the application of PD biomarkers for biosimilar development.

Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (I) A Randomized Trial with PCSK9 Inhibitors.

US Food and Drug Administration (FDA) guidance outlines how biosimilars can be developed based on pharmacokinetic (PK) and pharmacodynamic (PD) similarity study data in lieu of a comparative clinical efficacy study. There is a paucity of PD comparability studies in biosimilar development, leaving open questions about how best to plan these studies. To that end, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants to evaluate approaches to address information gaps, inform analysis best practices, and apply emerging technologies in biomarker characterization. Seventy-two healthy participants (n = 8 per arm) received either placebo or one of four doses of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab (15-100 mg) or evolocumab (21-140 mg) to evaluate the maximum change from baseline (ΔPDmax ) and the baseline-adjusted area under the effect curve (AUEC) for the biomarkers low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in serum. We investigated approaches to minimize variability in PD measures. Coefficient of variation was lower for LDL-C than apoB at therapeutic doses. Modeling and simulation were used to establish the dose-response relationship and provided support that therapeutic doses for these products are adequately sensitive and are on the steep part of the dose-response curves. Similar dose-response relationships were observed for both biomarkers. ΔPDmax plateaued at lower doses than AUEC. In summary, this study illustrates how pilot study data can be leveraged to inform appropriate dosing and data analyses for a PK and PD similarity study.

Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (II) A Randomized Trial with IL-5 Antagonists.

The US Food and Drug Administration (FDA) guidance describes how pharmacodynamic (PD) biomarkers can be used to address residual uncertainty and demonstrate no clinically meaningful differences between a proposed biosimilar and its reference product without relying on clinical efficacy end point(s). Pilot studies and modeling can inform dosing for such PD studies. To that end, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants to evaluate approaches to address information gaps, inform best practices for analysis of biomarker samples and study results, and apply emerging technologies in biomarker characterization. Seventy-two healthy participants (n = 8 per arm) received either placebo or 1 of 4 doses of the interleukin-5 inhibitors mepolizumab (3-24 mg) or reslizumab (0.1-0.8 mg/kg). A clinical study using doses lower than approved therapeutic doses was combined with modeling and simulation to evaluate the dose-response relationship of the biomarker eosinophils. There was no dose-response relationship for eosinophil counts due to variability, although the mepolizumab 24 mg and reslizumab 0.8 mg/kg doses showed clear effects. Published indirect-response models were used to explore eosinophil data across doses from this study and the unstudied therapeutic doses. Simulations were used to calculate typical PD metrics, such as baseline-adjusted area under the effect curve and maximum change from baseline. The simulation results demonstrate sensitivity of eosinophils as a PD biomarker and indicate doses lower than the approved doses would have PD responses overlapping with variability in the placebo arm. The simulation results further highlight the utility of model-based approaches in supporting use of PD biomarkers in biosimilar development.

A metagenomic analysis for combination therapy of multiple classes of antibiotics on the prevention of the spread of antibiotic-resistant genes.

Antibiotics used systemically to treat infections may have off-target effects on the gut microbiome, potentially resulting in the emergence of drug-resistant bacteria or selection of pathogenic species. These organisms may present a risk to the host and spread to the environment with a risk of transmission in the community. To investigate the risk of emergent antibiotic resistance in the gut microbiome following systemic treatment with antibiotics, this metagenomic analysis project used next-generation sequencing, a custom-built metagenomics pipeline, and differential abundance analysis to study the effect of antibiotics (ampicillin, ciprofloxacin, and fosfomycin) in monotherapy and different combinations at high and low doses, to determine the effect on resistome and taxonomic composition in the gut of Balb/c mice. The results showed that low-dose monotherapy treatments showed little change in microbiome composition but did show an increase in expression of many antibiotic-resistant genes (ARGs) posttreatment. Dual combination treatments allowed the emergence of some conditionally pathogenic bacteria and some increase in the abundance of ARGs despite a general decrease in microbiota diversity. Triple combination treatment was the most successful in inhibiting emergence of relevant opportunistic pathogens and completely suppressed all ARGs after 72 h of treatment. The relative abundances of mobile genetic elements that can enhance transmission of antibiotic resistance either decreased or remained the same for combination therapy while increasing for low-dose monotherapy. Combination therapy prevented the emergence of ARGs and decreased bacterial diversity, while low-dose monotherapy treatment increased ARGs and did not greatly change bacterial diversity.