Mehul Mehta's research while affiliated with U.S. Food and Drug Administration and other places
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Publications (49)
Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for...
This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride...
The FDA has concluded that the efficacy of drugs approved for the treatment of partial onset seizures (POS) in adults can be extrapolated to pediatric patients 1 month of age and above and that independent efficacy trials in this pediatric population are no longer needed. This manuscript focuses on the dosing, pharmacokinetic, exposure‐response, an...
Modified release (MR) products are engineered to release drugs in a controlled manner so that certain drug release pattern or pharmacokinetic profile can be generated to meet specific clinical needs. The US Food and Drug Administration is the federal agency responsible for new drug approval. This chapter provides readers with an overview of a devel...
Several challenges are associated with rare disease drug development in neurology. In this article, we summarize the U.S. Food and Drug Administration’s experience with clinical drug development for rare neurological diseases and discuss clinical pharmacology’s critical contributions to drug development for rare diseases. We used publicly available...
Sitagliptin is an antihyperglycemic drug used in adults for the treatment of diabetes Type 2. Literature data and in-house experiments were applied in this monograph to assess whether methods based on the Biopharmaceutics Classification System (BCS) could be used to assess the bioequivalence of solid immediate-release (IR) oral dosage forms contain...
Pediatric labeling information for novel atypical antipsychotics can be significantly delayed as the result of time lag between initial drug approval in adults and the completion of pediatric clinical trials. This delay can lead health care providers to rely on limited evidence-based literature to make critical therapeutic decisions for pediatric p...
Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered “highly soluble”...
Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin’s Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transp...
Objective:
To evaluate the performance of the individual Positive and Negative Symptom Scale (PANSS) items, and to assess the feasibility of using a shortened version of the PANSS as an alternative regulatory endpoint for evaluating the efficacy of drugs to treat schizophrenia.
Design:
Data from 32 randomized, placebo-controlled, multiregional t...
Purpose:
To explore the use of a multistate repeated, time-to-categorical event model describing the frequency, severity and duration of migraines.
Methods:
Subject level data from patients in placebo arms from two efficacy trials for migraine-preventive treatments were used. Models were developed using NONMEM 7.3. A survival model was combined...
Importance
Facilitating the development of safe and effective medications for schizophrenia is a public health imperative.
Objectives
To evaluate the association of shortening randomized clinical trial (RCT) duration with the modification of the Positive and Negative Syndrome Scale (PANSS) for the design of RCTs of medications for schizophrenia an...
In this monograph, literature data is reviewed to evaluate the feasibility of waiving in vivo bioequivalence (BE) testing and instead applying the Biopharmaceutics Classification System (BCS) based methods to the approval of immediate-release (IR) solid oral dosage forms containing moxifloxacin hydrochloride as the sole active pharmaceutical ingred...
The development of modified-release (MR) drug products aims to address a clinical need such as improving patient compliance. There are multiple pathways and development strategies for the registration and approval of MR products. The development strategy of an MR product is usually dependent on the availability and pharmacokinetic/pharmacodynamics...
The European Federation of Pharmaceutical Sciences (EUFEPS) and American Association of Pharmaceutical Scientists (AAPS) have collaborated since 2015 to organize international conferences to support global harmonization of regulatory requirements for bioequivalence (BE) assessment. This collaboration has resulted in three Global Bioequivalence Harm...
Objective:
Concerns of increasing placebo response and declining treatment effect in acute schizophrenia trials have been reported for new drug applications (NDAs) submitted to the US Food and Drug Administration (FDA) during an 18-year period from 1991 through January 2009 (ie, the pre-2009 period). Current exploratory analyses provide an update...
Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release (IR) solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the FDA, WHO and...
Despite agreement that early-onset schizophrenia is continuous with the adult-onset form, quantitative relationships between antipsychotic exposure and clinical response are relatively unexplored in adolescents, compared to adults. Clinical efficacy data from second-generation antipsychotic development programs (N=5951 adults and N=1035 adolescents...
Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver...
In this article, a special case for bioequivalence evaluation of oral formulations is discussed. Drug formulations with the different forms of active moieties (e.g., free base and salt) may yield different dissolution characteristics and thus differ in absorption at elevated gastric pH. However, routine bioequivalence trials using subjects with nor...
Early onset schizophrenia or “adolescent schizophrenia” has a global incidence ranging up to 4% of all schizophrenia cases. Clinical data from antipsychotic programs were collected from new drug applications submitted to the US Food and Drug administration from 1993 to 2015. A placebo response‐dropout model was developed to describe the time course...
This study was performed to identify an efficacious dosing regimen for U.S. Food and Drug Administration approval of topiramate for initial monotherapy in pediatric patients aged 2-9 years diagnosed with partial onset seizures and primary generalized tonic-clonic seizures using a pharmacometric bridging approach. The approval of topiramate in monot...
The Global Bioequivalence Harmonization Initiative (GBHI) was launched by the Network on Bioavailability and Biopharmaceutics (BABP) under the auspices of European Federation for Pharmaceutical Sciences (EUFEPS) several years ago. Since 2015, EUFEPS in collaboration with the American Association of Pharmaceutical Scientists (AAPS) has organized thr...
Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To clarify the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimal...
The FDA guidance on application of the Biopharmaceutics Classification System (BCS) for waiver of in-vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created world-wide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry towards its implementation and further expansion....
Bioequivalence (BE) is considered one of the key questions in new and generic drug product development and registration worldwide. However, the regulations and jurisdiction vary from country to country and continent to continent. Harmonization of regulatory requirements and criteria for BE determination may avoid unnecessary repetition of BE studie...
This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the hig...
The aim of the study was to evaluate the exposure–response (E–R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this an...
Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index,...
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as...
Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its ther...
Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system...
To facilitate specific product development, AUCs obtained over time intervals of interest, known as partial AUC, can be used for bioavailability and bioequivalence assessment. Partial AUC, which describes shapes of pharmacokinetic profiles, is most useful in products with complicated release mechanisms where traditional bioequivalence variables suc...
Biowaiver is defined as FDA waiving the requirement for the in vivo bioavailability/bioequivalence studies. This chapter discusses the following biowaivers: (a) For drug products where bioavailability is self-evident e.g., solutions, (b) Biowaivers in situations where one can rely on in vitro methods instead of in vivo for assessing bioavailability...
Clinical pharmacology as an interdisciplinary science is unique in its capacity and the diversity of the methods and approaches it can provide to derive dosing recommendations in various subpopulations. This article illustrates cases where an integrated clinical pharmacology approach was used to derive dosing recommendations for psychiatry drugs wi...
The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submis...
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and reg...
Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity.
This paper is a summary report of the American Association of Pharmaceutical Scien...
Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This an...
The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty-four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages < or = 4 years or > 4 years, respectively, 4 times a day for 4 days. Dense PK sampling was perfor...
The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at...
The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS clas...
The current BSC guidance issued by the FDA allows for biowaivers based on conservative criteria. Possible new criteria and class boundaries are proposed for additional biowaivers based on the underlying physiology of the gastrointestinal tract. The proposed changes in new class boundaries for solubility and permeability are as follows: 1. Narrow th...
Bioavailability and/or bioequivalence studies play a key role in the drug development period for both new drug products and their generic equivalents. For both, these studies are also important in the postapproval period in the presence of certain manufacturing changes. Like many regulatory studies, the assessment of bioavailability and bioequivale...
Citations
... In the fasted stomach, the ionized form of levamisole is the predominant species, while in the small intestine, approximately half of the drug is present as the non-ionized form. The predicted log p-value of levamisole is 2.36 [98,99]. In one study, the plasma and urine concentrations of levamisole were measured in 10 healthy volunteers (including seven men and three women) after a single dose of 150 mg levamisole. ...
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... For lipid compartments, the trend is somewhat more complicated, with an initial increase from 10% to 15% at birth to 20% to 25% in late infancy, and then a decrease to 10% to 15% until adolescence. The greater total body space and foreign body space in neonates and neonate's results in lower plasma drug concentrations for these respective compartmentalized drugs when administered by weight [54]. The opposite is true for lipophilic compounds. ...
... The length of the review (147 pages) or a strongly held negative view on aducanumab's approval decision may have contributed to the lack of interest in reading the full review. Even though multiple articles 11,12,13 were published by the FDA staff to explain the rationale for the accelerated approval decision, the recommendation from the Office of Clinical Pharmacology at the FDA was a regular/full approval, not an accelerated approval. Therefore, it is necessary to summarize the key points that were used to support the regular/full approval recommendation in a scientific journal article. ...
... Several publications have described the clinical pharmacology studies that support the development of orphan drugs. 12,20,21 However, a comparison between drugs for rare diseases and common diseases has not been done to understand if select clinical pharmacology studies were performed during drug development and how the information translated into the labeling at the time of approval. Here, we aimed to compare the labeling of orphan and nonorphan NMEs approved between 2017 and 2019 to understand the availability of recommendations and information from the select clinical pharmacology studies at the time of approval. ...
... [6][7][8][9] All information was thoroughly reviewed and organized using the same approach as in recent biowaiver monographs such as sitagliptin and moxifloxacin. [10][11] Solubility studies on levocetirizine pure substance and its release from the test formulation (Azal Pharmaceutical Company, Khartoum) were carried out at the Al Ribat University in Khartoum. To determine its solubility in buffer solutions over the pH range 1.2−6.8, ...
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... S. Kalaria и соавт. (2021) показали, что на первом этапе планирования исследований для обоснования экстраполяции на детскую популяцию данных, полученных в исследованиях с участием взрослых, используют оценку сходства развития заболевания [25]. Для проведения указанной оценки применяли механистические модели, а именно нелинейный подход к моделированию смешанных эффектов. ...
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... The solubility of CBZ in water was measured to range from 0.14 to 0.27 mg/L at 25°C (26) According to the Biopharmaceutics Classification System (BCS), CBZ is a BCS class II (poorly soluble; highly permeable) compound where dissolution is the rate limiting factor for its absorption (27). Due to its high pKa (11.8 or 14), no ionization of CBZ is expected within the physiological pH range (28). A previous study (5) showed that CBZ solubility in neonatal or infant FaSSGF, where the BS concentration was, respectively, 25% (20 µM) or 75% (60 µM) of adult values (80 µM), was significantly reduced at the lower BS concentrations. ...
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... Metformin HCl belongs to Biopharmaceutics Classification System (BCS) Class III. In other words, it is highly soluble in water, but its oral bioavailability is approximately 50% [8]. It also has a mean plasma elimination half-life of between 1.5 and 4.5 h [9,10]. ...
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... The extent to which different indications influence the duration of clinical trials is as yet under-researched. However, few papers have looked at study durations of single indications and found different study lengths [30][31][32]. With our results, we were able to confirm this once again, across all 14 ATC indication areas (e.g., ONCIM clinical studies took 3.27 years longer (p < 0.000) compared to healthy individuals/phase 1 clinical studies, SENS clinical studies only took 0.56 years longer than our control group (p < 0.000)). ...
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... Moxifloxacin (MFX) is a broad-spectrum fluoroquinolone antibiotic that inhibits a range of gram-negative and gram-positive organisms, anaerobes, and atypical bacteria [14]. Based on the Biopharmaceutics Classification System, it belongs to class I with high solubility and high permeability [15]. Clarithromycin (CLM), a macrolide antibiotic, has activity against gram-negative and gram-positive pathogens, atypical organisms, and some anaerobes [16]. ...
