Population Pharmacokinetics of Fasinumab in Healthy Volunteers and Patients With Pain Due to Osteoarthritis of the Knee or Hip.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1 mg/kg IV or 0.1-0.3 mg/kg SC)/fixed dose (9-12 mg IV or 1-12 mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1 mg SC dose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Subcutaneous Administration of Monoclonal Antibodies: Pharmacology, Delivery, Immunogenicity, and Learnings From Applications to Clinical Development.

Subcutaneous (s.c.) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared with intravenous (i.v.) infusion through shorter administration times, made possible by convenient, patient-centric devices. A deeper understanding of clinical pharmacology principles related to efficacy and safety of s.c.-administered mAbs over the past decade has streamlined s.c. product development. This review presents learnings from key constituents of the s.c. mAb development pathway, including pharmacology, administration variables, immunogenicity, and delivery devices. Restricted mAb transportation through the hypodermis explains their incomplete absorption at a relatively slow rate (pharmacokinetic (PK)) and may impact mAb-cellular interactions and/or onset and magnitude of physiological responses (pharmacodynamic). Injection volumes, formulation, rate and site of injection, and needle attributes may affect PKs and the occurrence/severity of adverse events like injection-site reactions or pain, with important consequences for treatment adherence. A review of immunogenicity data for numerous compounds reveals that incidence of anti-drug antibodies (ADAs) is generally comparable across i.v. and s.c. routes, and complementary factors including response magnitude (ADA titer), persistence over time, and neutralizing antibody presence are needed to assess clinical impact. Finally, four case studies showcase how s.c. biologics have been clinically developed: (i) by implementation of i.v./s.c. bridging strategies to streamline PD-1/PD-L1 inhibitor development, (ii) through co-development with i.v. presentations for anti-severe acute respiratory syndrome-coronavirus 2 antibodies to support rapid deployment of both formulations, (iii) as the lead route for bispecific T cell engagers (BTCEs) to mitigate BTCE-mediated cytokine release syndrome, and (iv) for pediatric patients in the case of dupilumab.

Digital technologies: Innovations that transform the face of drug development.

Recently, digital health technologies (DHTs) and digital biomarkers have gained a lot of traction in clinical investigations, motivating sponsors, investigators, and regulators to discuss and implement integrated approaches for deploying DHTs. These new tools present new and unique challenges for optimal technology integration in clinical trial processes, including operational, ethical, and regulatory issues. In this paper, we gathered different perspectives to discuss challenges and perspectives from three different stakeholders: industry, US regulators, and a public-private partnership consortium. The complexities of DHT implementation, which include regulatory definitions, defining the scope of validation experiments, and the need for partnerships between BioPharma and the technology sectors, are highlighted. Most of these challenges are related to translation of DHT-derived measures into endpoints that are meaningful to clinicians and patients, participant safety, training, and retention and privacy of data. The example of the Wearable Assessments in the Clinic and Home in PD (WATCH-PD) study is discussed as an example that demonstrated the advantages of pre-competitive collaborations, which include early regulatory feedback, data sharing, and multistakeholder alignment. Future advances in DHTs are expected to spur device-agnostic measured development and incorporate patient reported outcomes in drug development. More efforts are needed to define validation experiments for a defined context of use, incentivize data sharing and development of data standards. Multistakeholder collaborations via precompetitive consortia will help facilitate broad acceptance of DHT-enabled measures in drug development.

In Vitro-In Vivo Correlation of Buprenorphine Transdermal Systems Under Normal and Elevated Skin Temperature.

PURPOSE: Application of external heat using a heating pad over buprenorphine transdermal system, Butrans® has been shown to increase systemic levels of buprenorphine in human volunteers. The purpose of this study was to perform in vitro permeation studies at normal as well as elevated temperature conditions to evaluate the correlation of in vitro data with the existing in vivo data. METHODS: In vitro permeation tests (IVPT) were performed on human skin from four donors. The IVPT study design was harmonized to a previously published clinical study design and skin temperature was maintained at either 32 ± 1 °C or 42 ± 1 °C to mimic normal and elevated skin temperature conditions, respectively. RESULTS: IVPT studies on human skin were able to demonstrate heat induced enhancement in flux and cumulative amount of drug permeated from Butrans® which was reasonably consistent with the corresponding enhancement observed in vivo. Level A in vitro-in vivo correlation (IVIVC) was established using unit impulse response (UIR) based deconvolution method for both baseline and heat arms of the study. The percent prediction error (%PE) calculated for AUC and Cmax values was less than 20%. CONCLUSIONS: The studies indicated that IVPT studies performed under the same conditions as those of interest in vivo may be useful for comparative evaluation of the effect of external heat on transdermal delivery system (TDS). Further research may be warranted to evaluate factors, beyond cutaneous bioavailability (BA) assessed using an IVPT study, that can influence plasma exposure in vivo for a given drug product.

Overview of Clinical Pharmacology Packages of New Drug Applications Approved for the Treatment of Rare Diseases.

There are more than 7000 rare diseases affecting approximately 30 million people in the United States. More than 90% of these diseases lack approved therapies. Several challenges face the development of "orphan drugs", such as the small populations of patients, high development costs, and long development timelines. This study evaluates clinical pharmacology assessments conducted during the development of drugs to treat rare diseases approved by the United States Food and Drug Administration in 2020 and 2021. Thirty-nine new drug applications (NDAs) have been identified and the associated regulatory reviews, approved labels, and approval letters were reviewed. Approximately, 95%, 74%, and 77% of these submissions contained at least one type of drug-drug interaction, the effect of organ impairment (hepatic and renal) on drug exposure, and QT liability assessment, respectively. Modeling and simulation approaches were utilized to address many clinical pharmacology questions, with population pharmacokinetic analyses used extensively in the evaluation of the effect of organ impairment on drug exposure and with physiologically based pharmacokinetic analyses used mainly in assessing drug interaction risks. In general, the clinical pharmacology packages in the NDAs of orphan drugs are not optimal and more work is needed to obtain a complete clinical pharmacology package at the time of initial approval to ensure the safe and effective use of these drugs across the spectrum of the target patient population. This study provides insights into the clinical pharmacology studies needed for drugs to treat rare diseases and would help both the regulators and drug developers to identify challenges and opportunities in conducting clinical pharmacology assessments for drugs developed to treat rare diseases.

Assessing the Combined Public Health Impact of Pharmaceutical Interventions on Pandemic Transmission and Mortality: An Example in SARS CoV-2.

To assess the combined role of anti-viral monoclonal antibodies (mAbs) and vaccines in reducing severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) transmission and mortality in the United States, an agent-based model was developed that accounted for social contacts, movement/travel, disease progression, and viral shedding. The model was calibrated to coronavirus disease 2019 (COVID-19) mortality between October 2020 and April 2021 (aggressive pandemic phase), and projected an extended outlook to estimate mortality during a less aggressive phase (April-August 2021). Simulated scenarios evaluated mAbs for averting infections and deaths in addition to vaccines and aggregated non-pharmaceutical interventions. Scenarios included mAbs as a treatment of COVID-19 and for passive immunity for postexposure prophylaxis (PEP) during a period when variants were susceptible to the mAbs. Rapid diagnostic testing paired with mAbs was evaluated as an early treatment-as-prevention strategy. Sensitivity analyses included increasing mAb supply and vaccine rollout. Allocation of mAbs for use only as PEP averted up to 14% more infections than vaccine alone, and targeting individuals ≥ 65 years averted up to 37% more deaths. Rapid testing for earlier diagnosis and mAb use amplified these benefits. Doubling the mAb supply further reduced infections and mortality. mAbs provided benefits even as proportion of the immunized population increased. Model projections estimated that ~ 42% of expected deaths between April and August 2021 could be averted. Assuming sensitivity to mAbs, their use as early treatment and PEP in addition to vaccines would substantially reduce SARS-CoV-2 transmission and mortality even as vaccination increases and mortality decreases. These results provide a template for informing public health policy for future pandemic preparedness.

Trends in FDA Transporter-Based Post-Marketing Requirements and Commitments Over the Last Decade.

Characterizing interactions between new molecular entities (NMEs) and drug transporters is a critical element of drug development that helps in assessing potential transporter-based drug-drug interactions (DDIs). However, not all NME new drug applications (NDAs) include a full characterization of NMEs transporter-based DDIs, which necessitates the issuance of post-marketing requirement (PMR)/post-marketing commitment (PMC) by the US Food and Drug Administration (FDA) to characterize these potential interactions. The objective of this analysis is to identify trends in transporter-based PMRs/PMCs issued by the FDA between 2012 and 2021. A decrease in the number of transporter-based PMRs/PMCs was observed from 2012 to 2016 and an increasing trend in the number of PMRs/PMCs was observed after 2017. The majority of these transporter-based PMRs/PMCs requested clinical evaluation (48%), some requested in vitro assessment (38%), and 2.5% requested modeling and simulation assessment. Most of the PMRs/PMCs requested evaluation of NMEs as perpetrator with the efflux transporters, P-gp and/or BCRP (53%). Forty-eight percent of the PMRs/PMCs were fulfilled with 67% resulted in labeling updates. On average, 2.5 years were needed for the information related to PMRs/PMCs to show in NMEs labeling. In conclusion, this analysis highlights the increased emphasis from the FDA on proper characterization of transporter-based DDI and call for the need of early characterization of NMEs-transporters interaction before initial NDA approval.

Investigator Impact on Reproducibility of Drug Bioavailability in Stratum Corneum Sampling by Tape Stripping.

PURPOSE: Skin sampling by tape stripping measures the local bioavailability of topical drug products in the stratum corneum (SC). The goal of the current study was to evaluate the impact of different investigators in studies that utilize a tape stripping protocol designed to minimize investigator variability. METHODS: Two open-label clinical studies compared two lidocaine patches and a diclofenac patch and solution in twelve healthy volunteers. The mass of drug was determined in SC samples collected on tape strips at three time points following product removal in duplicate by two investigators. Investigator results were compared with each other and with results for the diclofenac solution measured by another laboratory using a similar protocol. RESULTS: For drug mass, the geometric mean ratio comparing two investigators is within the acceptable bioequivalence interval for most measurement times and drug products. Drug uptake into the SC from the diclofenac solution was not statistically different from that determined in another laboratory. The average flux from the SC over the clearance intervals for the four drug products correspond well with flux measurements from in vitro permeation tests. CONCLUSIONS: Results from different investigators are reproducible within the limitations of measurement variability, which can be managed by increasing volunteer numbers.

Evaluation of in vitro/in vivo correlations for three fentanyl transdermal delivery systems using in vitro skin permeation testing and human pharmacokinetic studies under the influence of transient heat application.

The value of developing an in vitro/in vivo correlation (IVIVC) is substantial in biopharmaceutical drug development because once the model is developed and validated, an in vitro method may be used to efficiently assess and predict drug product performance in vivo. In this study, three bioequivalent, matrix-type, fentanyl transdermal delivery systems (TDS) were evaluated in vitro using an in vitro permeation test (IVPT) and dermatomed human skin, and in vivo in human pharmacokinetic (PK) studies under harmonized study designs to evaluate IVIVC. The study designs included 1 h of transient heat application (42 ± 2°C) at either 11 h or 18 h after TDS application to concurrently investigate the influence of heat on drug bioavailability from TDS and the feasibility of IVPT to predict the effects of heat on TDS in vivo. Level A (point-to-point) and Level C (single point) IVIVCs were evaluated by using PK-based mathematical equations and building IVIVC models between in vitro fraction of drug permeation and in vivo fraction of drug absorption. The study results showed that the three differently formulated fentanyl TDS have comparable (p > 0.05) heat effects both in vitro and in vivo. In addition, the predicted steady-state concentration (Css) from in vitro flux data and the observed Css in vivo showed no significant differences (p > 0.05). However, the effects of heat on enhancement of fentanyl bioavailability observed in vivo were found to be greater compared to those observed in vitro for all three drug products, resulting in a weak prediction of the impact of heat on bioavailability from the in vitro data. The results from the current work suggest that while IVPT can be a useful tool to evaluate the performance of fentanyl TDS in vivo with a relatively good predictability at a normal temperature condition and to compare the effect of heat on drug delivery from differently formulated TDS, additional testing measures would enhance the ability to predict the heat effects in vivo with a lower prediction error.

Randomised trial of azithromycin to eradicate Ureaplasma in preterm infants.

OBJECTIVE: To test whether azithromycin eradicates Ureaplasma from the respiratory tract in preterm infants. DESIGN: Prospective, phase IIb randomised, double-blind, placebo-controlled trial. SETTING: Seven level III-IV US, academic, neonatal intensive care units (NICUs). PATIENTS: Infants 240-286 weeks' gestation (stratified 240-266; 270-286 weeks) randomly assigned within 4 days following birth from July 2013 to August 2016. INTERVENTIONS: Intravenous azithromycin 20 mg/kg or an equal volume of D5W (placebo) every 24 hours for 3 days. MAIN OUTCOME MEASURES: The primary efficacy outcome was Ureaplasma-free survival. Secondary outcomes were all-cause mortality, Ureaplasma clearance, physiological bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age, comorbidities of prematurity and duration of respiratory support. RESULTS: One hundred and twenty-one randomised participants (azithromycin: n=60; placebo: n=61) were included in the intent-to-treat analysis (mean gestational age 26.2±1.4 weeks). Forty-four of 121 participants (36%) were Ureaplasma positive (azithromycin: n=19; placebo: n=25). Ureaplasma-free survival was 55/60 (92% (95% CI 82% to 97%)) for azithromycin compared with 37/61 (61% (95% CI 48% to 73%)) for placebo. Mortality was similar comparing the two treatment groups (5/60 (8%) vs 6/61 (10%)). Azithromycin effectively eradicated Ureaplasma in all azithromycin-assigned colonised infants, but 21/25 (84%) Ureaplasma-colonised participants receiving placebo were culture positive at one or more follow-up timepoints. Most of the neonatal mortality and morbidity was concentrated in 21 infants with lower respiratory tract Ureaplasma colonisation. In a subgroup analysis, physiological BPD-free survival was 5/10 (50%) (95% CI 19% to 81%) among azithromycin-assigned infants with lower respiratory tract Ureaplasma colonisation versus 2/11 (18%) (95% CI 2% to 52%) in placebo-treated infants. CONCLUSION: A 3-day azithromycin regimen effectively eradicated respiratory tract Ureaplasma colonisation in this study. TRIAL REGISTRATION NUMBER: NCT01778634.

Effect of Controlled Heat Application on Topical Diclofenac Formulations Evaluated by In Vitro Permeation Tests (IVPT) Using Porcine and Human Skin.

PURPOSE: Heat therapy is widely used for pain relief and may unintentionally be used in conjunction with pain relieving topical formulations. The purpose of this study was to evaluate the influence of heat on the permeation of diclofenac through porcine and human skin, comparing four marketed products. METHODS: In vitro permeation tests (IVPT) were performed on porcine skin from a single miniature pig and human skin from three donors. Skin temperature was maintained at either 32 ± 1°C or 42 ± 1°C to mimic normal and elevated skin temperature conditions, respectively. RESULTS: IVPT studies on porcine and human skin were able to demonstrate heat-induced enhancement in flux and cumulative amount of drug permeated from the four diclofenac products. The pivotal data showed the most significant heat-induced enhancement for the solution, followed by the patch and two gels in decreasing order of significance based on p values. Diclofenac solution showed the highest flux and cumulative amount permeated at both baseline and elevated skin temperature compared to the patch and gels. CONCLUSIONS: The studies demonstrated that exposure to heat can alter drug permeation from topical formulations, but the increased levels are not expected to lead to systemic concentrations that are of concern. Formulation design and excipients can influence drug permeation at elevated skin temperature.

Dosage Regimens for Meropenem in Children with Pseudomonas Infections Do Not Meet Serum Concentration Targets.

There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high-risk children and adults. We evaluated this observation in children using literature studies conducted in infants and children. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). A population pharmacokinetic model was fit to the data and then used to simulate the recommended dosing regimens and estimate the proportion of subjects achieving recommended target exposures. A two-compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. The US Food and Drug Administration (FDA)-approved dosing regimens achieved targets in ~ 90% or more of subjects less than 3 months of age for organisms with minimum inhibitory concentration (MIC)'s of 2 and 4 mg/L; however, only 68.4% and 41.7% of subjects older than 3 months and weighing < 50 kg achieved target exposures for organisms with MIC's of 2 and 4 mg/L, respectively [Correction added on January 23, 2020, after first online publication: "> 3 months" corrected to "less than 3 months".]. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Simulation studies were used to explore the impact of changing dose, dosing interval, and infusion duration on the likelihood of achieving therapeutic targets in these groups. Our findings illustrate that current dosing recommendations for children over 3 months of age fail to meet therapeutic targets in an unacceptable fraction of patients. Further investigation is needed to develop new dosing strategies in these patients.

The Sensitivity of In Vitro Permeation Tests to Chemical Penetration Enhancer Concentration Changes in Fentanyl Transdermal Delivery Systems.

Chemical penetration enhancers (CPEs) are frequently incorporated into transdermal delivery systems (TDSs) to improve drug delivery and to reduce the required drug load in formulations. However, the minimum detectable effect of formulation changes to CPE-containing TDSs using in vitro permeation tests (IVPT), a widely used method to characterize permeation of topically applied drug products, remains unclear. The objective of the current exploratory study was to investigate the sensitivity of IVPT in assessing permeation changes with CPE concentration modifications and subsequently the feasibility of IVPT's use for support of quality control related to relative CPE concentration variation in a given formulation. A series of drug-in-adhesive (DIA) fentanyl TDSs with different amounts of CPEs were prepared, and IVPT studies utilizing porcine and human skin were performed. Although IVPT could discern TDSs with different amounts of CPE by significant differences in flux profiles, maximum flux (Jmax) values, and total permeation amounts, the magnitudes of the CPE increment needed to see such significant differences were very high (43-300%) indicating that IVPT may have limitations in detecting small changes in CPE amounts in some TDSs. Possible reasons for such limitations include formulation polymer and/or other excipients, type of CPE, variability associated with IVPT, skin type used, and disrupted stratum corneum (SC) barrier effects caused by CPEs.

Validated UHPLC-MS/MS method for quantification of doxycycline in abdominal aortic aneurysm patients.

AIM: There is a strong evidence that doxycycline can benefit abdominal aortic aneurysms patients because of its ability to inhibit matrix metalloproteinase enzymes. There is a need for a specific quantification method for doxycycline in these patients. We report herein the development and validation of a selective, specific, simple and rapid UHPLC-MS/MS method for doxycycline. RESULTS: The assay was linear (r2 > 0.994) over a concentration range of 0.010-7.005 µg/ml. This validated method has good lower limit of quantification (LLOQ) (10 ng/ml), accuracies (89.1-103.4%), precision (≤7.0%) and extraction recoveries (95.8%). Doxycycline was stable during short- and long-term storage. CONCLUSION: The assay is reliable and has been successfully applied to serum samples obtained from the patients of N-TA3CT clinical study.

In vitro-in vivo correlations for nicotine transdermal delivery systems evaluated by both in vitro skin permeation (IVPT) and in vivo serum pharmacokinetics under the influence of transient heat application.

The in vitro permeation test (IVPT) has been widely used to characterize the bioavailability (BA) of compounds applied on the skin. In this study, we performed IVPT studies using excised human skin (in vitro) and harmonized in vivo human serum pharmacokinetic (PK) studies to evaluate the potential in vitro-in vivo correlation (IVIVC) of nicotine BA from two, matrix-type, nicotine transdermal delivery systems (TDS). The study designs used for both in vitro and in vivo studies included 1h of transient heat (42±2°C) application during early or late time periods post-dosing. The goal was to evaluate whether any IVIVC observed would be evident even under conditions of heat exposure, in order to investigate further whether IVPT may have the potential to serve as a possible surrogate method to evaluate the in vivo effects of heat on the bioavailability of a drug delivered from a TDS. The study results have demonstrated that the BA of nicotine characterized by the IVPT studies correlated with and was predictive of the in vivo BA of nicotine from the respective TDS, evaluated under the matched study designs and conditions. The comparisons of single parameters such as steady-state concentration, heat-induced increase in partial AUCs and post-treatment residual content of nicotine in TDS from the in vitro and in vivo data sets showed no significant differences (p≥0.05). In addition, a good point-to-point IVIVC (Level A correlation) for the entire study duration was achieved by predicting in vivo concentrations of nicotine using two approaches: Approach I requiring only an in vitro data set and Approach II involving deconvolution and convolution steps. The results of our work suggest that a well designed IVPT study with adequate controls can be a useful tool to evaluate the relative effects of heat on the BA of nicotine from TDS with different formulations.

Antibody-Drug Conjugates: Pharmacokinetic/Pharmacodynamic Modeling, Preclinical Characterization, Clinical Studies, and Lessons Learned.

Antibody-drug conjugates are an emerging class of biopharmaceuticals changing the landscape of targeted chemotherapy. These conjugates combine the target specificity of monoclonal antibodies with the anti-cancer activity of small-molecule therapeutics. Several antibody-drug conjugates have received approval for the treatment of various types of cancer including gemtuzumab ozogamicin (Mylotarg®), brentuximab vedotin (Adcetris®), trastuzumab emtansine (Kadcyla®), and inotuzumab ozogamicin, which recently received approval (Besponsa®). In addition to these approved therapies, there are many antibody-drug conjugates in the drug development pipeline and in clinical trials, although these fall outside the scope of this article. Understanding the pharmacokinetics and pharmacodynamics of antibody-drug conjugates and the development of pharmacokinetic/pharmacodynamic models is indispensable, albeit challenging as there are many parameters to incorporate including the disposition of the intact antibody-drug conjugate complex, the antibody, and the drug agents following their dissociation in the body. In this review, we discuss how antibody-drug conjugates progressed over time, the challenges in their development, and how our understanding of their pharmacokinetics/pharmacodynamics led to greater strides towards successful targeted therapy programs.

LC-MS determination of fentanyl in human serum and application to a fentanyl transdermal delivery pharmacokinetic study.

AIM: Fentanyl is an opioid agonist used for acute and chronic pain management. In this report, a highly sensitive and simple LC-MS/MS method using Hydrophilic Interaction Chromatography (HILIC) column was validated and used for fentanyl quantification in human serum. RESULTS: The isocratic mobile phase was composed of acetonitrile: 10 mM ammonium formate buffer (pH = 3.2; 90:10, v/v). The assay was linear over a concentration range of 10-10,000 pg/ml. The accuracy of the validation method ranged from 93.2 to 107%, and the precision was within 6.4%. Fentanyl was stable during short- and long-term storage. CONCLUSION: The assay has been successfully applied to serum samples obtained from healthy subjects of a fentanyl transdermal pharmacokinetic study.