scholarly journals Pharmacogenetic perspectives in improving pharmacokinetic profiles for efficient bioequivalence trials with highly variable drugs: a review

2020 ◽  
pp. IPK02
Author(s):  
Pai-Jung Huang ◽  
Yunsheng Hsieh ◽  
Yan-Wen Huang ◽  
Li Ding ◽  
Chong Liu ◽  
...  
Keyword(s):  
Generic Drugs ◽  
Pharmacokinetic Studies ◽  
Metabolizing Enzymes ◽  
Highly Variable Drugs ◽  
Drug Products ◽  
Branded Drug ◽  
Coefficient Of Variability ◽  
Acceptance Limits ◽  
Study Designs ◽  
Screening Approaches

Conducting bioequivalence trials under traditional crossover study designs without exposing a large number of healthy volunteers to demonstrate two highly variable (%coefficient of variability greater than 30) test/reference (branded) drug products in different formulations to meet the standard 90% confidence interval criteria of relevant pharmacokinetic metrics between 0.80 and 1.25 and to maintain the consumer risk smaller than 5% has been a challenging task. Genetic polymorphisms encoding key drug-metabolizing enzymes can significantly influence absorption, distribution, metabolism and elimination of many highly variable generic drugs after administration. This article briefly reviews the case studies and examples of utilizing pharmacogenetic screening approaches in the recent literature to alleviate the resources and ethical burden of recruiting larger numbers of subjects in bioequivalence trials needed to perform pharmacokinetic studies for formulations of highly variable drug products without widening the bioequivalence acceptance limits.

scholarly journals Sequencing of the Canine Cytochrome P450 CYP2C41 Gene and Genotyping of Its Polymorphic Occurrence in 36 Dog Breeds

2021 ◽  
Vol 8 ◽  
Author(s):  
Emre Karakus ◽  
Clarissa Prinzinger ◽  
Silke Leiting ◽  
Joachim Geyer
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Gene Deletion ◽  
Homologous Sequence ◽  
Pharmacokinetic Studies ◽  
Metabolizing Enzymes ◽  
Genomic Level ◽  
Very High

Cytochrome P450 (CYP) drug metabolizing enzymes play an important role in efficient drug metabolism and elimination. Many CYPs are polymorphic and, thereby, drug metabolism can vary between individuals. In the case of canine CYP2C41, gene polymorphism was identified. However, as the first available canine genome sequences all were CYP2C41 negative, this polymorphism could not be clarified at the genomic level. The present study provides an exact characterization of the CYP2C41 gene deletion polymorphism at the genomic level and presents a PCR-based genotyping method that was used for CYP2C41 genotyping of 1,089 individual subjects from 36 different dog breeds. None of the Bearded Collie, Bernese Mountain, Boxer, Briard, French Bulldog or Irish Wolfhound subjects had the CYP2C41 gene in their genomes. In contrast, in the Chinese Char-Pei, Siberian Husky, Schapendoes and Kangal breeds, the CYP2C41 allele frequency was very high, with values of 67, 57, 43, and 34%, respectively. Interestingly, the site of gene deletion was identical for all CYP2C41 negative dogs, and all CYP2C41 positive dogs showed highly homologous sequence domains upstream and downstream from the CYP2C41 gene. CYP2C41 genotyping can now be routinely used in future pharmacokinetic studies in canines, in order to identify genetically-based poor or extensive drug metabolizers. This, together with more extensive in vitro drug screening for CYP2C41 substrates will help to determine the clinical relevance of CYP2C41, and to optimize drug treatment. Although the relative abundance of the CYP2C41 protein in the canine liver seems to not be very high, this CYP could substantially contribute to hepatic drug metabolism in dogs expressing CYP2C41 from both alleles and, when CYP2C41 shows higher catalytic activity to a given drug than other hepatic metabolic enzymes.

When are drug combinations justified?

1980 ◽  
Vol 18 (10) ◽  
pp. 37-40
Keyword(s):  
Metabolic Disease ◽  
World Wide ◽  
Fixed Ratio ◽  
Drug Combinations ◽  
World Health ◽  
Active Ingredients ◽  
Dose Ratio ◽  
Drug Products ◽  
Branded Drug ◽  
The World

Drug combinations contain two or more active ingredients in fixed doses in a single preparation; the dose-ratio is determined by the manufacturer. Among over 240 preparations on the World Health Organisation’s model list of ‘essential’ drugs, there are only 7 drug combinations - less than 3%.1 By contrast, of more than 2, 2000 branded drug products listed in MIMS,2 nearly half are fixed-ratio combinations, although the proportion varies widely between therapeutic groups - 10% for metabolic disease, 70% for respiratory and gastro-intestinal conditions.3 More than one-third of all new drug products introduced world-wide in 1978 were combinations.4

Therapeutic Equivalence and the Generic Competition Paradox

2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Munirul Haque Nabin ◽  
Vijay Mohan ◽  
Aaron Nicholas ◽  
Pasquale M. Sgro
Keyword(s):  
Simple Model ◽  
Generic Drug ◽  
Generic Drugs ◽  
Large Body ◽  
Medical Community ◽  
Therapeutic Equivalence ◽  
Generic Competition ◽  
Branded Drug ◽  
Fda Approval ◽  
Generic Products

Abstract Following the passage of the Waxman-Hatch Act (1984), FDA approval for a generic drug requires the establishment of bio-equivalence between the generic drug and an FDA approved branded drug. However, a large body of evidence in the medical community suggests that bio-equivalence does not guarantee therapeutic equivalence; in some instances the lack of therapeutic equivalence can lead to fatal consequences for patients switching to generic products. In this paper, we construct a simple model to analyze the implications of therapeutic non-equivalence between branded and generic drugs. We show, theoretically and empirically, that this distinction can provide a plausible explanation of the generic competition paradox.

Recent developments in US law: Remedies and damages for improper patent listings in the FDA's Orange Book

10.5912/jcb29 ◽  
1969 ◽  
Vol 9 (3) ◽  
Author(s):  
Daniel G Brown
Keyword(s):  
Price Competition ◽  
Generic Drugs ◽  
Pharmaceutical Product ◽  
Pharmaceutical Companies ◽  
White House ◽  
Drug Products ◽  
The Us ◽  
Recent Developments ◽  
The Usa ◽  
Orange Book

The Drug Price Competition and Patent Term Restoration Act (Publ. No. 98-417, 98 Stat. 1585 (1984)), commonly known as the Hatch–Waxman Act (the Act) provides the statutory framework by which most generic drugs are approved for marketing in the USA. Most provisions in the Act concern the standards and procedures the US Food and Drug Administration (FDA) must follow to approve generic drugs. A relatively small number of the provisions, however, create a framework for resolving patent disputes between the brand and generic pharmaceutical companies. These provisions have been the subject of much recent activity, in the US Courts, in Congress, in the FDA itself and in the White House. Much of the activity revolves around a publication by FDA entitled Approved Drug Products with Therapeutic Equivalence Evaluations, known colloquially as the Orange Book.Under present FDA practice, the mere listing of a patent in the Orange Book corresponding to a brand pharmaceutical product invokes a number of statutory provisions that confer valuable exclusivity rights on the brand company, and also possibly on one or more generic companies. This situation creates a strong incentive for patentees and brand pharmaceutical companies to list patents in the Orange Book. A number of recent court cases have addressed the remedies and damages available when the listing is found to be improper. Thus far, the most successful means to challenge or prevent improper listings has been through private and governmental enforcement of the antitrust laws.

scholarly journals A Review of Population Pharmacokinetic Studies of Levetiracetam

2020 ◽  
Author(s):  
Ziran Li ◽  
Chenyu Wang ◽  
Xiao Zhu ◽  
Zheng Jiao
Keyword(s):  
Renal Function ◽  
Target Population ◽  
Volume Of Distribution ◽  
Drug Clearance ◽  
The Body ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Apparent Clearance ◽  
Adults And Children ◽  
Study Designs

Background: Levetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy. Objective: The aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore identified influencing covariates. Methods: We systematically searched PubMed and Embase databases from inception to June 30, 2020. The information on study designs, target population, model characteristics, and identified covariates were summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults. Results: A total of 14 studies were included, among which two involved neonates, four involved children, two involved both children and adults, and six involved only adults. The median value of apparent clearance for children (0.074 [range: 0.038 to 0.079] L/h/kg) was higher than that for adults (0.054 [range: 0.039 to 0.061] L/h/kg). Body weight was found to influence the apparent clearance and volume of distribution significantly, whereas renal function influenced the clearance. Likewise, co-administration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9 to 22%, whereas coadministration with valproate acid decreased it by 18.8%. Conclusion: Levetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women.

scholarly journals Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives

2020 ◽  
Vol 117 (27) ◽  
pp. 16009-16018 ◽  
Author(s):  
Ling Zou ◽  
Peter Spanogiannopoulos ◽  
Lindsey M. Pieper ◽  
Huan-Chieh Chien ◽  
Wenlong Cai ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Azo Dye ◽  
Pharmacokinetic Studies ◽  
Unintended Effects ◽  
Drug Products ◽  
Intestinal Drug Absorption ◽  
High Concentrations ◽  
Gut Microbial Community ◽  
Selection Of

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R−N=N−R′) dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.

The bioequivalence of highly variable drugs and drug products

2005 ◽  
Vol 43 (10) ◽  
pp. 485-498 ◽  
Author(s):  
K.K. Midha ◽  
M.J. Rawson ◽  
J.W. Hubbard
Keyword(s):  
Highly Variable Drugs ◽  
Drug Products

IUPAC/CITAC Guide: Investigating out-of-specification test results of chemical composition based on metrological concepts (IUPAC Technical Report)

2012 ◽  
Vol 84 (9) ◽  
pp. 1939-1971 ◽  
Author(s):  
Ilya Kuselman ◽  
Francesca Pennecchi ◽  
Cathy Burns ◽  
Aleš Fajgelj ◽  
Paolo de Zorzi
Keyword(s):  
Chemical Composition ◽  
Metrological Traceability ◽  
Drug Analysis ◽  
Stability Study ◽  
Test Results ◽  
Validation Data ◽  
Drug Products ◽  
Technical Report ◽  
Acceptance Limits ◽  
Actual Change

A metrological background for investigating out-of-specification (OOS) test results of chemical composition is discussed. When an OOS test result is identified, it is important to determine its root causes and to avoid reoccurrence of such results. An investigation of the causes based on metrological concepts is proposed. It includes assessment of validation data of the measurement process and its metrological traceability chains, evaluation of measurement uncertainty, and related producer’s and consumer’s risks. This approach allows distinguishing between OOS test results that indicate an actual change in chemical composition of an analyzed object, and OOS test results that are metrologically related with a certain confidence probability, i.e., caused by measurement problems, while the analyzed object still meets the specification requirements at the time of testing. Practical examples illustrating applications of the described approach in environ-mental and food analysis, as well in drug analysis and stability study of drug products, are described. Acceptance limits, warning and action lines for the test results, and corresponding producer’s and consumer’s risks are discussed.

scholarly journals A UPLC-MS/MS METHOD DEVELOPMENT AND VALIDATION FOR THE ESTIMATION OF SOFOSBUVIR FROM HUMAN PLASMA

2016 ◽  
Vol 9 (1) ◽  
pp. 30 ◽  
Author(s):  
Darshan Bhatt ◽  
B. Rajkamal
Keyword(s):  
Chromatographic Separation ◽  
Method Development ◽  
Internal Standard ◽  
Ultra Performance Liquid Chromatography ◽  
Pharmacokinetic Studies ◽  
Solution Stability ◽  
Tandem Mass ◽  
Stability Studies ◽  
Liquid Chromatography Tandem Mass ◽  
Acceptance Limits

Objective: The present work aimed to develop a simple, rapid, specific and precise ultra-performance liquid chromatography-tandem mass spectrophotometric (LC–MS/MS) validated method for quantification of sofosbuvir and internal standard (ISTD) Sofosbuvir-d3 in human plasma.Methods: Samples prepared by employing liquid-liquid extraction (LLE) using 2.5 ml of ethyl acetate. Chromatographic separation was achieved on Gemini 5µ C18, 50 x 4.6 mm column using a mixture of 0.1% (v/v) formic acid in water to methanol at a ratio of 30:70 v/v as the mobile phase. The flow rate was 0.50 ml/min. The LC eluent was split, and approximately 0.1 ml/min was introduced into Tandem mass spectrometer using turbo Ion Spray interface at 325 °C. Quantitation was performed by transitions of 428.35/279.26 (m/z) for sofosbuvir and 431.38/282.37 (m/z) for sofosbuvir-d3.Results: The concentrations of ten working standards showed linearity between 4.063 to 8000.010ng/ml (r2 ≥ 0.9985). Chromatographic separation was achieved within 2 min. The average extraction recoveries of three quality control concentrations were 75.36% for sofosbuvir and were within the acceptance limits. The coefficient of variation was ≤15% for intra-and inter-batch assays. The %CV of ruggedness ranges 0.35% and 3.09%. The % stability of short term and long term stock solution stability studies was found to be 97.25% and 98.81% respectively.Conclusion: The results obtained for specificity, linearity, accuracy, precision, ruggedness and stability studies were within the acceptance limits. Thus the validated economical method was applied for pharmacokinetic studies of sofosbuvir.

Individual and Average Bioequivalence of Highly Variable Drugs and Drug Products

1997 ◽  
Vol 86 (11) ◽  
pp. 1193-1197 ◽  
Author(s):  
Kamal K. Midha ◽  
Maureen J. Rawson ◽  
John W. Hubbard
Keyword(s):  
Highly Variable Drugs ◽  
Average Bioequivalence ◽  
Drug Products
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