In recent years, physiologically based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics. It has been demonstrated to be ...informative and helpful to quantify the modification in drug exposure due to specific physio‐pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug–drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism‐based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism‐based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software. The aim of this report was to establish confidence in each CYP‐specific modulator file so they can be used in the future for the prediction of DDIs involving new victim compounds. Our evaluation of these PBPK models suggested that they can be successfully used to evaluate DDIs in untested scenarios. The only noticeable exception concerned a quinidine inhibitor model that requires further improvement. Additionally, other important aspects such as model validation criteria were discussed.
The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on ...whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra‐subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow‐therapeutic‐index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second‐generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%–111%) applied to NTI drugs. Intra‐subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra‐subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non‐bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.
Many antibiotics carry caution stickers that warn against alcohol consumption. Data regarding concurrent use are sparse. An awareness of data that address this common clinical scenario is important ...so health care professionals can make informed clinical decisions and address questions in an evidence-based manner. The purpose of this systematic review was to determine the evidence behind alcohol warnings issued for many common antimicrobials. The search was conducted from inception of each database to 2018 using PubMed, Medline via Ovid, and Embase. It included studies that involved interactions, effects on efficacy, and toxicity/adverse drug reactions (ADR) due to concomitant alcohol consumption and antimicrobials. All interactions were considered in terms of three components: (i) alteration in pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials and/or alcohol, (ii) change in antimicrobial efficacy, and (iii) development of toxicity/ADR. Available data support that oral penicillins, cefdinir, cefpodoxime, fluoroquinolones, azithromycin, tetracycline, nitrofurantoin, secnidazole, tinidazole, and fluconazole can be safely used with concomitant alcohol consumption. Data are equivocal for trimethoprim-sulfamethoxazole. Erythromycin may have reduced efficacy with alcohol consumption, and doxycycline may have reduced efficacy in chronic alcoholism. Alcohol low in tyramine may be consumed with oxazolidinones. The disulfiram-like reaction, though classically associated with metronidazole, occurs with uncertain frequency and with varied severity. Cephalosporins with a methylthiotetrazole (MTT) side chain or a methylthiodioxotriazine (MTDT) ring, ketoconazole, and griseofulvin have an increased risk of a disulfiram-like reaction. Alcohol and antimicrobial interactions are often lacking evidence. This review questions common beliefs due to poor, often conflicting data and identifies important knowledge gaps.
•PNIPAAm-g-chitosan/PCL-Diol-b-PU core-shell nanofibers were synthesized.•Paclitaxel and 5-FU anticancer drugs were incorporated into the nanofibers.•The nanofibers surface was coated by magnetic ...gold nanoparticles.•The nanofibers was examined toward 4T1 breast cancer cells in vitro and in vivo.•The inhibition of tumor growth by the nanofibers during 10 days was obtained.
The poly (ε-caprolactonediol) based polyurethane (PCL-Diol-b-PU)/poly(N-isopropylacrylamide)-grafted-chitosan (PNIPAAm-g-chitosan) core-shell nanofibers were synthesized via coaxial electrospinning process. Paclitaxel and 5-FU anticancer drugs were incorporated into the core of nanofibers. The nanofibers surface was coated using magnetic gold nanoparticles and the potential of synthesized nanofibers was investigated for the sustained release of paclitaxel and 5-FU toward 4T1 breast cancer cells death in vitro and in vivo. The synthesized magnetic nanoparticles were characterized using SEM, TEM, XRD and DLS analysis. The surface morphology of nanofibers was studied under various applied voltage and different shell flow rates. The paclitaxel and 5-FU release profiles from nanofibers were examined under acidic and physiological pH. The maximum 4T1 cell killing was found to be 78% using magnetic gold coated-nanofibers in the presence of external magnetic field. The SEM images after incubation of nanofibers in 4T1 breast cancer cells indicated the well adhesion of cells on the nanofibers surface. The in vivo studies showed that the tumor volume did not change during 10 days. The minimum increase in tumor volume was obtained using paclitaxel and 5-FU loaded-nanofibers coated by the magnetic gold nanoparticles. The obtained results demonstrated the high therapeutic efficiency of synthesized nanofibrous carrier toward breast cancer treatment.
Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of ...an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration-time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal Peff estimates and jejunal Peff measurements determined directly using the single-pass perfusion double balloon technique. On average, Peff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal Peff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.
Serum IgG concentration-time data were analyzed using non-compartmental methods to generate PK parameters. Results Seventeen patients (9 females, mean age of 30.6 years, all Caucasian) were included ...in the PK analysis; 15 of them provided PK samples for both weekly and biweekly regimens.
The two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 ...chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.
Background Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.¹ ² ...Deucravacitinib binds the unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind the catalytic domain. Deucravacitinib showed superior efficacy vs placebo in a phase 2 trial in SLE (NCT03252587).³ This analysis assessed the pharmacokinetics (PK), selectivity profile compared to JAK inhibitors, and exposure-response (E-R) relationship for efficacy and safety of deucravacitinib in SLE. Methods In the phase 2 trial, patients with active SLE were randomized 1:1:1:1 to placebo or deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD). PK analysis included pooled concentration data from 266 SLE patients and 328 phase 1 participants. IC50 was determined by in vitro whole blood assays and plotted against PK profiles. E-R analyses included data from 356 patients. Logistic regression analyses assessed the relationship between deucravacitinib exposure and probability of achieving efficacy endpoints and safety events at weeks 32 and 48. Results Deucravacitinib PK in SLE patients was not meaningfully different from that in phase 1 participants. At 12 mg QD, deucravacitinib Cmax was 8-fold lower than JAK 1/3 IC50 and 47-fold lower than JAK 2/2 IC50 (figure 1). In the E-R analyses, the probability of achieving SRI(4) and BICLA at week 32 increased with increasing deucravacitinib CminSS, with 3 mg BID providing near-maximal response. The E-R relationship for infection and infestation was relatively flat, while skin and subcutaneous tissue disorders increased with increasing deucravacitinib CminSS. These E-R relationships were similar at week 48. Conclusions Deucravacitinib PK in SLE patients is not meaningfully different from that in phase 1 participants. At clinically relevant exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 vs JAK 1/2/3. The deucravacitinib E-R relationships are well characterized for various efficacy endpoints and safety events. Abstract LP-182 Figure 1 Plasma concentration-time profile of deucravacitinib, baricitinib, tofacitinib, and upadacitinib along with their respective whole blood IC50 curves Figure omitted. See PDF References Armstrong A, et al. J Am Acad Dermatol 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol 2022 Nov 11 (Epub ahead of print).
Summary In the recent years, eight tyrosine kinase inhibitors (TKIs) have been approved for cancer treatment and numerous are under investigation. These drugs are rationally designed to target ...specific tyrosine kinases that are mutated and/or over-expressed in cancer tissues. Post marketing study commitments have been made upon (accelerated) approval such as additional pharmacokinetic studies in patients with renal- or hepatic impairment, in children, additional interactions studies and studies on the relative or absolute bioavailability. Therefore, much information will emerge on the pharmacokinetic behavior of these drugs after their approval. In the present manuscript, the pharmacokinetic characteristics; absorption, distribution, metabolism and excretion (ADME), of the available TKIs are reviewed. Results from additional studies on the effect of drug transporters and drug–drug interactions have been incorporated. Overall, the TKIs reach their maximum plasma levels relatively fast; have an unknown absolute bioavailability, are extensively distributed and highly protein bound. The drugs are primarily metabolized by cytochrome P 450 (CYP) 3A4 with other CYP-enzymes playing a secondary role. They are predominantly excreted with the feces and only a minor fraction is eliminated with the urine. All TKIs appear to be transported by the efflux ATP binding-cassette transports B1 and G2. Additionally these drugs can inhibit some of their own metabolizing enzymes and transporters making steady-state metabolism and drug–drug interactions both complex and unpredictable. By understanding the pharmacokinetic profile of these drugs and their similarities, factors that influence drug exposure will be better recognized and this knowledge may be used to limit sub- or supra-therapeutic drug exposure.
•An exploratory randomized, controlled trial of baloxavir marboxil and favipiravir in COVID-19 patients were conducted.•The free drug concentrations of baloxavir acid and favipiravir are generally ...lower than their respective EC50 values.•Add-on either baloxavir or favipiravir to the current standard treatment resulted in no additional antiviral benefit.
Background: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients.
Methods: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544).
Results: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 μM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 μM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group.
Conclusions: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.
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