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CPT: Pharmacometrics & Systems... May 2021Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be... (Review)
Review
Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically-based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit-for-purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making.
Topics: Administration, Cutaneous; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Humans; Models, Biological; Skin; Therapeutic Equivalency
PubMed: 33547863
DOI: 10.1002/psp4.12600 -
European Review For Medical and... May 2023OBJECTIVE: Neuropathic pain is regulated by several metabolites of the kynurenine pathway (KYNA-kynurenic acid, and QA-quinolinic acid). Diclofenac exerts analgesic and...
OBJECTIVE: Neuropathic pain is regulated by several metabolites of the kynurenine pathway (KYNA-kynurenic acid, and QA-quinolinic acid). Diclofenac exerts analgesic and anti-hyperalgesic effects and also alters KYNA levels, indicating a potential for therapy. We aimed to assess the nociceptive effects of different doses of diclofenac treatment in a rat model of neuropathic pain and to determine potential relationships with KYNA and QA levels (Graphical Abstract). MATERIALS AND METHODS: Twenty-eight Sprague-Dawley rats were divided into four groups: 40 mg/kg/day diclofenac (high-dose), 20 mg/kg/day diclofenac (normal-dose), non-treatment, and sham. Except for the sham group, the others underwent partial sciatic nerve ligation (left). Baseline (day 0) and post-treatment (day 3) KYNA and QA levels were measured. Allodynia and pain detection were assessed with the von Frey and hot plate tests. RESULTS: Baseline findings were similar in all groups. Compared to baseline, the non-treatment group had significantly worse allodynia on day 3. Baseline and post-treatment von Frey results (left) remained similar in the normal-dose diclofenac group (p=0.336); however, this benefit was not observed in the high-dose group. Relative to baseline, normal-dose diclofenac recipients had significantly higher KYNA concentration (p=0.046) and KYNA-to-QA ratio (p=0.028) on day 3. CONCLUSIONS: Our results show that 3-day therapy with 20 mg/kg/day diclofenac can improve nociceptive findings in neuropathic pain, and that this effect may be associated with increased KYNA or KYNA-to-QA ratio. The lack of dose-dependent effects may be associated with potential adverse influences of exceedingly high diclofenac dosage.
Topics: Rats; Animals; Diclofenac; Kynurenine; Hyperalgesia; Rats, Sprague-Dawley; Nociception; Neuralgia; Sciatic Nerve
PubMed: 37203850
DOI: 10.26355/eurrev_202305_32334 -
BMC Complementary Medicine and Therapies Dec 2022Among the most commonly consumed non-steroidal anti-inflammatory drugs (NSAID) is Diclofenac (Dic), especially in low-income countries due to its high efficiency and...
BACKGROUND
Among the most commonly consumed non-steroidal anti-inflammatory drugs (NSAID) is Diclofenac (Dic), especially in low-income countries due to its high efficiency and affordable price. However, the continuous administration of Diclofenac may induce toxic effects on various body organs including the liver and kidney. Caffeine (Caf) (1,3,7-trimethylxanthine) is a pharmacologically active alkaloid type with antioxidant and anti-inflammatory actions.
AIM
The current study aims to evaluate the ameliorative effect of Caffeine against Dic-induced hepato-renal toxicity and damage.
METHODS
Twenty-four male albino rats type were assigned randomly into four groups (n = 6): (Group 1): Control group, (Group 2): Six male rats were exposed to Dic 10 mg/kg intraperitoneally (I.P) for 28 days, (Group 3): Six male rats were exposed to Caf (15 mg/kg orally) for 28 days; (Groups 4): Six male rats were exposed to Dic (10 mg/kg, i.p) + Caf (15 mg/kg, orally) for 28 days. Histopathological study and various biological parameters were estimated among the four groups including hemoglobin (Hb%) red blood cells (RBCs), Hematocrit (HT%), total leucocyte count (WBCs), lipid peroxidation (LPO), glutathione peroxidase (GPx), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine, tumor necrosis factor-α (TNF-α), and nitric oxide (NO).
RESULTS
The administration of Diclofenac resulted in significant deteriorations in the histopathological findings and estimated biological parameters. Whereas, daily Caffeine administration ameliorated Diclofenac-induced toxicity in the kidney and liver by three mechanisms including antioxidant, anti-inflammatory, and DNA damage inhibition.
CONCLUSION
The current study demonstrated the promising ameliorative and protective effects of Caffeine against Diclofenac-induced hepatic and renal injury.
Topics: Male; Rats; Animals; Diclofenac; Caffeine; Liver; Chromosome Aberrations; Anti-Inflammatory Agents
PubMed: 36482339
DOI: 10.1186/s12906-022-03802-y -
Topical bioequivalence: Experimental and regulatory considerations following formulation complexity.International Journal of Pharmaceutics May 2022Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA...
Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA guideline, for simple formulations, BE may be demonstrated by documenting the qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence. Nevertheless, when addressing complex semisolids, equivalence regarding local availability should also be demonstrated. The purpose of this study is to pursue this strategy using two opposite scenarios: a simple dimetindene maleate 1 mg/g gel formulation and a diclofenac diethylammonium 23.2 mg/g emulgel, representing a complex formulation. For both formulations, Q1/Q2 test (TP) and reference products (RP) were used. Rheology, in vitro release (IVRT) and in vitro permeation methods (IVPT) were developed and validated for both products. For the dimetindene formulation, equivalence pertaining to Q4 was established. However, high variability was observed for some rheology endpoints, especially for the different RP batches. Therefore, equivalence could not be established for Q3 as per EMA requirements. Can some rheology endpoints be waived? Can we establish reasonable criteria that are overall feasible for generic manufacturers and at the same time safe for the patient? An attempt was made to propose a wider acceptance range based on the inter-batch variability of the RP. For that, the rationale presented in the EMA guideline on bioequivalence for highly variable products was used. For the diclofenac formulation, Q3 equivalence was likewise not established. Q4 equivalence was only found for some batch combinations and when applying a wider acceptance criterion (75-133%). Furthermore, IVPT equivalence also failed to be demonstrated. Nevertheless, since the TP displays an equivalent pharmacokinetic profile compared to the RP, the observed Q3, Q4 and local availability differences are not expected to be clinically significant. This study draws attention to an effective search to determine the most appropriate strategy for assessing topical bioequivalence on a case-by-case basis.
Topics: Diclofenac; Dimethindene; Drugs, Generic; Humans; In Vitro Techniques; Therapeutic Equivalency
PubMed: 35358644
DOI: 10.1016/j.ijpharm.2022.121705 -
Current Rheumatology Reviews 2020Diclofenac and curcumin is anticipated to have synergistic action. Hence, topical route of administration can be used in minimizing the issues with oral administration...
BACKGROUND
Diclofenac and curcumin is anticipated to have synergistic action. Hence, topical route of administration can be used in minimizing the issues with oral administration of both drugs.
OBJECTIVE
This research aims at formulation of controlled release dosage form containing curcumin microspheres and diclofenac diethylamine and then incorporating it into gel formulation for treatment of inflammation associated with rheumatoid arthritis.
METHODS
Curcumin microspheres were prepared, optimized and assayed. Gel containing microspheres was formulated and evaluated for physicochemical parameters like spreadability and viscosity. In vitro and ex vivo diffusion studies were carried out followed by evaluation of efficacy. Efficacy of the developed formulation was evaluated for anti-inflammatory activity.
RESULTS
Particle size, Zeta potential, pH, spreadability and viscosity of optimized Batch F1 was found to be in range 0.5 µm - 5 µm,-27.9 mV, 6.2, 105 g cm/s and 7500 cps respectively. In vitro diffusion of developed gel of diclofenac diethylamine and curcumin was found to be 92.16 ± 0.0040 % in 3 h and 92.54 ± 0.0036 % in 12 h as compared to 79.57 ± 0.004 % diffusion in 2 h for marketed gel, thus showing controlled delivery of curcumin.
CONCLUSION
Decreased inflammation in formulation treated group by 72.53% and 50.75% in marketed treated group was seen. Thus the formulation developed showed prolonged activity as well as better anti-inflammatory activity.
Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Curcumin; Delayed-Action Preparations; Diclofenac; Diethylamines; Drug Delivery Systems; Male; Microspheres; Rats; Rats, Wistar
PubMed: 31738154
DOI: 10.2174/1573397115666191105142827 -
Chemical Research in Toxicology Feb 2020To investigate the respective roles of cytochromes P450 2C9 and 3A in drug oxidation in human livers, the pharmacokinetics of -warfarin and diclofenac were analyzed...
Different Roles of Human Cytochrome P450 2C9 and 3A Enzymes in Diclofenac 4'- and 5-Hydroxylations Mediated by Metabolically Inactivated Human Hepatocytes in Previously Transplanted Chimeric Mice.
To investigate the respective roles of cytochromes P450 2C9 and 3A in drug oxidation in human livers, the pharmacokinetics of -warfarin and diclofenac were analyzed after intravenous administrations in chimeric mice that had been transplanted with human hepatocytes. P450 2C9 was metabolically inactivated in the humanized mice by orally pretreating them with tienilic acid. After intravenous administration of -warfarin, a significant difference in the concentration-time profiles of the primary metabolite 7-hydroxywarfarin between untreated mice and mice treated with tienilic acid was observed. In contrast, there were no apparent differences in the profiles for -warfarin between the treated and untreated groups. The mean values of the maximum concentrations () and the areas under the plasma concentration versus time curves (AUC) for 7-hydroxywarfarin were significantly lower (22 and 16% of the untreated values, respectively) in the treated group. This presumably resulted from suppressed P450 2C9 activity in the primary oxidative metabolism in the treated group. After diclofenac administration, plasma levels of diclofenac, 5-hydroxydiclofenac, and diclofenac acylglucuronide were roughly similar in pretreated and untreated mice. However, the mean and AUC values for 4'-hydroxydiclofenac were significantly lower (38 and 53% of the untreated group, respectively) in the treated group. The reported value of ∼0.8 for the fraction of -warfarin metabolized to 7-hydroxywarfarin mediated by P450 2C9 in systems was similar to the value implied by the present humanized-liver mouse model pretreated with tienilic acid in which the AUC of 7-hydroxywarfarin was reduced by 84%. In contrast, the fractions of diclofenac metabolized to 4'-hydroxydiclofenac in and experiments were inconsistent. These results suggested that humanized-liver mice orally treated with tienilic acid might constitute an model for metabolically inactivated P450 2C9 in human hepatocytes transplanted into chimeric mice. Moreover, diclofenac, a typical P450 2C9 probe substrate, was cleared differently and in humanized-liver mice .
Topics: Animals; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Diclofenac; Hepatocytes; Humans; Hydroxylation; Mice; Transplantation Chimera
PubMed: 31854189
DOI: 10.1021/acs.chemrestox.9b00446 -
Journal of Ocular Pharmacology and... Dec 2016To compare the effects of topical diclofenac and betamethasone on postoperative inflammation after combined sutureless cataract and vitreoretinal surgery in patients... (Clinical Trial)
Clinical Trial Comparative Study
PURPOSE
To compare the effects of topical diclofenac and betamethasone on postoperative inflammation after combined sutureless cataract and vitreoretinal surgery in patients with macular hole (MH), epiretinal membrane (ERM), diabetic macular edema (DME), and rhegmatogenous retinal detachment (RRD).
METHODS
The study involved 180 eligible eyes that underwent the combined surgery, followed by treatment with topical diclofenac (n = 100) or betamethasone (n = 80) for 12 weeks. Maximum postoperative inflammation index (maxPOI), assessed by laser flare-cell meter, and intraocular pressure (IOP) were monitored. The relationships between maxPOI and total operation time or number of endophotocoagulations during surgery were investigated.
RESULTS
Postoperative inflammation peaked at 2 weeks and decreased thereafter in all 4 diseases, without significant differences between 2 treated groups. Postoperative IOP in MH and ERM was significantly higher in the betamethasone group. In DME and RRD, a greater number of endophotocoagulations increased maxPOI in both diclofenac and betamethasone groups, while longer operation time increased maxPOI only in diclofenac groups.
CONCLUSIONS
In MH and ERM, topical diclofenac and betamethasone equally suppressed postoperative inflammation after the combined surgery, although diclofenac better controlled postoperative IOP. In DME and RRD, both drugs were equally effective in suppressing inflammation and controlling IOP, but diclofenac showed weaker suppression following longer operation.
Topics: Administration, Topical; Aged; Betamethasone; Cataract; Diclofenac; Female; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Vitrectomy; Vitreous Hemorrhage
PubMed: 27754737
DOI: 10.1089/jop.2016.0099 -
Archives of Pharmacal Research Jan 2015Aceclofenac is one of the most popular analgesic and anti-inflammatory drugs used for the relief of pain, rheumatoid arthritis, and osteoarthritis. To date, no...
Aceclofenac is one of the most popular analgesic and anti-inflammatory drugs used for the relief of pain, rheumatoid arthritis, and osteoarthritis. To date, no intravenous preparation of aceclofenac has been developed because of its poor water solubility. In this study, to investigate its absolute bioavailability and metabolism in rats, aceclofenac was dissolved in a sterile aqueous solution containing urea (20 %) and trisodium citrate (10 %), and administered via oral (20 mg/kg) and intravenous (10 mg/kg) routes. Blood samples were taken serially, and aceclofenac and its three major metabolites (4'-hydroxydiclofenac, 4'-hydroxyaceclofenac, and diclofenac) were measured by HPLC-MS/MS. The absolute oral bioavailability of aceclofenac was approximately 15 %. Diclofenac and 4'-hydroxydiclofenac were the main metabolites in rats, in contrast to 4'-hydroxyaceclofenac in humans. The low bioavailability of aceclofenac is likely due to extensive metabolism, and bioavailability may be even lower if the drug were administered as a tablet, considering its low water solubility. This study provides complete time profiles of the plasma concentrations of aceclofenac and its metabolites in rats and highlights the difference in drug metabolism between rats and humans.
Topics: Administration, Intravenous; Administration, Oral; Animals; Biological Availability; Diclofenac; Male; Rats
PubMed: 24633464
DOI: 10.1007/s12272-014-0350-4 -
Journal of Pharmaceutical Sciences Feb 2016Degradation reactions on diclofenac-monoglycerides (3a,b), diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c), diclofenac (1), and diclofenac lactam (4) were performed...
Degradation reactions on diclofenac-monoglycerides (3a,b), diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c), diclofenac (1), and diclofenac lactam (4) were performed at 37 °C in isotonic buffer solutions (apparent pH range 1-8) containing varying concentrations of acetonitrile (ACN). The concentration remaining of each analyte was measured versus time. Diclofenac-monoglycerides and diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c) were both found to undergo facile and complete hydrolysis in pH 7.4 isotonic phosphate buffer/10% ACN. Under mildly acidic, neutral or alkaline conditions, diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c) had the fastest hydrolysis rate (t1/2 = 3.23 h at pH 7.4), with simultaneous formation of diclofenac lactam (4) and diclofenac (1). Diclofenac-monoglycerides (3a,b) hydrolyzed more slowly under the same conditions, to again yield both diclofenac (1) and diclofenac lactam (4). There was also transesterification of diclofenac-2-monoglyceride (3b) to its regioisomer, diclofenac-1-monoglyceride (3a) across the pH range. Diclofenac was shown to be stable in neutral or alkaline conditions but cyclized to form the lactam (4) in acidic conditions. Conversely, the lactam (4) was stable under acidic conditions but was converted to an unknown species under alkaline or neutral conditions.
Topics: Diclofenac; Esters; Hydrolysis; Polymers; Prodrugs
PubMed: 26540508
DOI: 10.1002/jps.24665 -
Drug Metabolism and Pharmacokinetics Dec 2016Aceclofenac has been used widely as a potent analgesic and anti-inflammatory drug. Aceclofenac is converted to 4'-hydroxyaceclofenac and diclofenac via CYP2C9-mediated...
Aceclofenac has been used widely as a potent analgesic and anti-inflammatory drug. Aceclofenac is converted to 4'-hydroxyaceclofenac and diclofenac via CYP2C9-mediated hydroxylation and hydrolysis, respectively. CYP2C9 also mediates the hydroxylation of diclofenac to yield 4'-hydroxydiclofenac and the hydrolysis of 4'-hydroxyaceclofenac to 4'-hydroxydiclofenac. We aimed to model the metabolism of aceclofenac in volunteers using a compartmental modeling approach. After an oral dose of 100 mg aceclofenac in volunteers, plasma concentrations of aceclofenac and its three metabolites were measured. The pharmacokinetics of aceclofenac and the sequential formation of its three metabolites were analyzed using ADAPT 5. The delay parameter shifted the plasma aceclofenac concentration-time profile to the right and provided a large improvement of fit. Two compartments were needed to fit the aceclofenac and 4'-hydroxyaceclofenac data, and one additional compartment was sufficient to describe the time courses of the generated plasma concentrations of diclofenac and 4'-hydroxydiclofenac. The metabolism rate constant for 4'-hydroxyaceclofenac was much greater than that for diclofenac. The generation rate constant of 4'-hydroxydiclofenac from diclofenac was greater than that of its generation from 4'-hydroxyaceclofenac. Our model fully describes the time course of plasma aceclofenac concentration as well as the formation and disposition of its three major metabolites in volunteers.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Healthy Volunteers; Humans; Male; Models, Biological; Young Adult
PubMed: 27839691
DOI: 10.1016/j.dmpk.2016.10.001