The story of the development of generic lenalidomide: How one company thwarted the Hatch-Waxman Act to generate billions of dollars in revenue.

Lenalidomide (Revlimid®) was originally approved by the Food and Drug Administration (FDA) in 2005, however, a generic version was not available until 2022. In that time, the price of lenalidomide has increased more than 20 times, and in 2021 alone, it accounted for >$5.8 billion dollars in Medicare Part D spending. This was a direct consequence of legal tactics employed by the manufacturer to thwart development of generic formulations of lenalidomide. In this report, we review the clinical development of lenalidomide, provide background on generic drug manufacturing in the United States (US), describe the steps that the manufacturer took to prevent entry of generic lenalidomide into the US market, and advocate for legislative reform of the FDA approval process and patent law protections in the US.

Perceptions of a virtual interview process for pharmacy residents during the COVID-19 pandemic: A multisite survey of residency candidates, preceptors, and residency program directors.

PURPOSE: To describe the perceptions of residency candidates, residency practitioners (current residents and preceptors), and residency program directors (RPDs) regarding a virtual interview process for pharmacy residency programs across multiple institutions. METHODS: In May 2021, an anonymous web-based questionnaire characterizing perceptions of the virtual interview process used during the coronavirus disease 2019 (COVID-19) pandemic was distributed to residency candidates, residency practitioners, and RPDs across 13 institutions. Quantitative responses measured on a 5-point Likert scale were summarized with descriptive statistics, and open-ended questions were analyzed using thematic qualitative methods. RESULTS: 236 residency candidates and 253 residency practitioners/RPDs completed the questionnaire, yielding response rates of 27.8% (236 of 848), and 38.1% (253 of 663), respectively. Overall, both groups perceived the virtual interview format positively. When asked whether virtual interviews should replace in-person interviews moving forward, 60.0% (18 of 30) of RPDs indicated they agreed or strongly agreed, whereas only 30.5% (61 of 200) of current preceptors/residents and 28.7% (66 of 230) of residency candidates agreed or strongly agreed. Thematic analysis of qualitative responses revealed that while virtual interviews were easier logistically, the lack of in-person interactions was a common concern for many stakeholders. Lastly, the majority (65.0%) of residency candidates reported greater than $1,000 in savings with virtual interviews. CONCLUSION: Virtual interviews offered logistical and financial benefits. The majority of RPDs were in favor of offering virtual interviews to replace in-person interviews, whereas the majority of residency candidates and practitioners preferred on-site interviews. As restrictions persist with the ongoing pandemic, our results provide insight into best practices for virtual pharmacy residency interviews.

Pharmacokinetics of perioperative FVIII in adult patients with haemophilia A: An external validation and development of an alternative population pharmacokinetic model.

INTRODUCTION: Haemophilia A patients require perioperative clotting factor replacement to limit excessive bleeding. Weight-based dosing of Factor VIII (FVIII) does not account for inter-individual pharmacokinetic (PK) variability, and may lead to suboptimal FVIII exposure. AIM: To perform an external validation of a previously developed population PK (popPK) model of perioperative FVIII in haemophilia A patients. METHODS: A retrospective chart review identified perioperative haemophilia A patients at the University of North Carolina (UNC) between April 2014 and November 2019. Patient data was used to externally validate a previously published popPK model proposed by Hazendonk. Based on these validation results, a modified popPK model was developed to characterize FVIII PK in our patients. Dosing simulations were performed using this model to compare FVIII target attainment between intermittent bolus (IB) and continuous infusion (CI) administration methods. RESULTS: A total of 521 FVIII concentrations, drawn from 34 patients, were analysed. Validation analyses revealed that the Hazendonk model did not fully capture FVIII PK in the UNC cohort. Therefore, a modified one-compartment model, with weight and age as covariates on clearance (CL), was developed. Dosing simulations revealed that CI resulted in improved target attainment by 16%, with reduced overall FVIII usage by 58 IU/kg, compared to IB. CONCLUSION: External validation revealed a previously published popPK model of FVIII did not adequately characterize UNC patients, likely due to differences in patient populations. Future prospective studies are needed to evaluate our model prior to implementation into clinical practice.

Immunotherapy Updates in Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance mechanisms and strengthening anti-tumor activity in the tumor microenvironment. In this review, we characterize the impact of immunotherapy on outcomes of advanced HCC, as well as the active clinical trials evaluating novel combination immunotherapy strategies. In particular, we discuss the efficacy of atezolizumab and bevacizumab as demonstrated in the IMbrave150 study, which created a new standard of care for the front-line treatment of advanced HCC. However, there are multiple ongoing trials that may present additional front-line treatment options depending on their efficacy/toxicity results. Furthermore, the preliminary data on the application of chimeric antigen receptor (CAR-T) cell therapy for treatment of HCC suggests this may be a promising option for the future of advanced HCC treatment.

Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains.

Cocaine (COC) is a psychostimulant with a high potential for abuse and addiction. Risk for COC use disorder is driven, in part, by genetic factors. Animal models of addiction-relevant behaviors have proven useful for studying both genetic and nongenetic contributions to drug response. In a previous study, we examined initial locomotor sensitivity to COC in genetically diverse inbred mouse strains. That work highlighted the relevance of pharmacokinetics (PK) in initial locomotor response to COC but was limited by a single dose and two sampling points. The objective of the present study was to characterize the PK and pharmacodynamics of COC and its metabolites (norcocaine and benzoylecgonine) in six inbred mouse strains (I/LnJ, C57BL/6J, FVB/NJ, BTBR T+ tf/J, LG/J and LP/J) that exhibit extreme locomotor responses to cocaine. Mice were administered COC at one of four doses and concentrations of cocaine, norcocaine and benzoylecgonine were analyzed in both plasma and brain tissue at 5 different time points. Initial locomotor sensitivity to COC was used as a pharmacodynamic endpoint. We developed an empirical population PK model that simultaneously characterizes cocaine, norcocaine and benzoylecgonine in plasma and brain tissues. We observed interstrain variability occurring in the brain compartment that may contribute to pharmacodynamic differences among select strains. Our current work paves the way for future studies to explore strain-specific pharmacokinetic differences and identify factors other than PK that are responsible for the diverse behavioral response to COC across these inbred mouse strains.

Phenelzine and Morphine Drug-Drug Interaction? A Literature Review.

The objectives of this manuscript are to describe a case report of a patient whose phenelzine maintenance therapy was discontinued due to concern for a phenelzine-morphine drug interaction, to review the available literature regarding the potential for this drug-drug interaction, and provide recommendations for this clinical scenario. A PubMed/MEDLINE literature search was conducted and all publications determined to be relevant to this case report were included. Literature describing in vitro data, case reports/human studies, and review articles concerning the interaction between morphine and monoamine oxidase inhibitors (MAOIs) were included. A total of 14 publications pertinent to the potential phenelzine-morphine interaction were included in this review including 5 in vitro studies, 4 human studies, and 6 review articles detailing the drug interaction profile between opioids and antidepressants. Of these publications, only a single case report of a potential drug interaction between morphine and phenelzine was identified. The literature suggesting a drug interaction between morphine and phenelzine is limited. The combination of phenelzine and morphine, with close monitoring for signs and symptoms of serotonin syndrome, is reasonable for patients with appropriate indications for both agents.

A Dried Blood Spot Analysis for Solithromycin in Adolescents, Children, and Infants: A Short Communication.

BACKGROUND: Solithromycin is a fourth-generation macrolide antibiotic with potential efficacy in pediatric community-acquired bacterial pneumonia. Pharmacokinetic (PK) studies of solithromycin in pediatric subjects are limited, therefore application of minimally invasive drug sampling techniques, such as dried blood spots (DBS), may enhance the enrollment of children in PK studies. The objectives of this study were to compare solithromycin concentrations in DBS with those in liquid plasma samples (LPS) and to quantify the effects of modeling DBS concentrations on the results of a population PK model. METHODS: Comparability analysis was performed on matched DBS and LPS solithromycin concentrations collected from two different phase 1 clinical trials of solithromycin treatment in children (clinicaltrials.gov #NCT01966055 and #NCT02268279). Comparability of solithromycin concentrations was evaluated based on DBS:LPS ratio, median percentage prediction error, and median absolute percentage prediction error. The effect of correcting DBS concentrations for both hematocrit and protein binding was investigated. In addition, a previously published population PK model (NONMEM) was leveraged to compare parameter estimates resulting from either DBS or LPS concentrations. RESULTS: A total of 672 paired DBS-LPS concentrations were available from 95 subjects (age: 0-17 years of age). The median (range) LPS and DBS solithromycin concentrations were 0.3 (0.01-12) mcg/mL and 0.32 (0.01-14) mcg/mL, respectively. Median percentage prediction error and median absolute percentage prediction error of raw DBS to LPS solithromycin concentrations were 5.26% and 22.95%, respectively. In addition, the majority of population PK parameter estimates resulting from modeling DBS concentrations were within 15% of those obtained from modeling LPS concentrations. CONCLUSIONS: Solithromycin concentrations in DBS were similar to those measured in LPS and did not require correction for hematocrit or protein binding.

The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children's Oncology Group.

BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity. OBJECTIVE: The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL. METHODS: A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m2 intravenously for four cycles during weeks 4-12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization. RESULTS: Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations. CONCLUSION: Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus.

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200-600 ng/mL.

External Evaluation of a Gentamicin Infant Population Pharmacokinetic Model Using Data from a National Electronic Health Record Database.

Gentamicin is a common antibiotic used in neonates and infants. A recently published population pharmacokinetic (PK) model was developed using data from multiple studies, and the objective of our analyses was to evaluate the feasibility of using a national electronic health record (EHR) database for further external evaluation of this model. Our results suggest that, with proper data capture procedures, EHR data can serve as a potential data source for external evaluation of PK models.

External Evaluation of Two Fluconazole Infant Population Pharmacokinetic Models.

Fluconazole is an antifungal agent used for the treatment of invasive candidiasis, a leading cause of morbidity and mortality in premature infants. Population pharmacokinetic (PK) models of fluconazole in infants have been previously published by Wade et al. (Antimicrob Agents Chemother 52:4043-4049, 2008, https://doi.org/10.1128/AAC.00569-08) and Momper et al. (Antimicrob Agents Chemother 60:5539-5545, 2016, https://doi.org/10.1128/AAC.00963-16). Here we report the results of the first external evaluation of the predictive performance of both models. We used patient-level data from both studies to externally evaluate both PK models. The predictive performance of each model was evaluated using the model prediction error (PE), mean prediction error (MPE), mean absolute prediction error (MAPE), prediction-corrected visual predictive check (pcVPC), and normalized prediction distribution errors (NPDE). The values of the parameters of each model were reestimated using both the external and merged data sets. When evaluated with the external data set, the model proposed by Wade et al. showed lower median PE, MPE, and MAPE (0.429 µg/ml, 41.9%, and 57.6%, respectively) than the model proposed by Momper et al. (2.45 µg/ml, 188%, and 195%, respectively). The values of the majority of reestimated parameters were within 20% of their respective original parameter values for all model evaluations. Our analysis determined that though both models are robust, the model proposed by Wade et al. had greater accuracy and precision than the model proposed by Momper et al., likely because it was derived from a patient population with a wider age range. This study highlights the importance of the external evaluation of infant population PK models.

Perceptions and Cost-Analysis of a Multiple Mini-Interview in a Pharmacy School Admissions Process.

OBJECTIVE: To improve the quality of admissions interviews for a doctor of pharmacy program, using a multiple mini-interview (MMI) in place of the standard interview. METHODS: Stakeholders completed an anonymous web-based survey. This study characterized perceptions of the MMI format across 3 major stakeholders (candidates, interviewers, admissions committee members) and included comparative cost estimates.Costs were estimated using human and facility resources from the 2012 cycle (standard format) and the 2013 cycle (MMI format). RESULTS: Most candidates (65%), interviewers (86%), and admissions committee members (79%) perceived the MMI format as effective for evaluating applicants, and most (59% of candidates, 84% of interviewers, 77% of committee members) agreed that the MMI format should be continued. Cost per candidate interviewed was $136.34 (standard interview) vs $75.30 (MMI). CONCLUSION: Perceptions of the MMI process were favorable across stakeholder groups, and this format was less costly per candidate interviewed.