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Model-informed drug repurposing: viral kinetic modelling to prioritize rational drug combinations for COVID-19. For example, some of these challenges were highlighted recently by the International Society for Aerosols in Medicine, as part of their call for consideration of inhaled delivery.[12] Several advanced drug delivery strategies can be applied much more rapidly than new drug development and do not need to be prohibitively expensive for global community programmes. Keywords: coronavirus; drug development; equitable access; repurposing; SARS-CoV-2 EN coronavirus drug development equitable access repurposing SARS-CoV-2 421 423 3 12/22/22 20230101 NES 230101 Given time, drug discovery programmes will undoubtedly yield highly potent drugs to form the basis of optimised COVID-19 regimens. [Extracted from the article]

Aims: Lopinavir (LPV) is not a first‐line regimen. According to recent WHO data, LPV usage in low‐ and middle‐income countries accounted for approximately 52% of the adult and 23% of the paediatric protease inhibitor market in 2017. Since LPV is a substrate for the SLCO1B1 (OATP1B1) transporter, the aim of this study was to assess the impact of SLCO1B1 polymorphisms (rs11045819, rs4149032 and rs4149056) on LPV trough plasma concentrations (Ctrough) in Serbian patients. Methods: Plasma samples from 104 HIV/AIDS Caucasians were collected. LPV Ctrough was quantified using liquid‐chromatography‐mass spectrometry. Genotyping was carried out using real‐time‐PCR‐based allelic discrimination. One‐way analysis of variance, t test and linear regression were used for data analysis. Results: The overall mean (SD) LPV Ctrough was 5885 ± 2755 ng/mL. Significant differences were between patients with different rs11045819 genotypes: CC (LPV median Ctrough = 6072 ng/mL, interquartile range (IQR) = 4318–7617 ng/mL), CA (LPV median Ctrough = 4987 ng/mL, IQR = 4300–6295 ng/mL) and AA (LPV median Ctrough = 3648 ng/mL, IQR = 1949–4072 ng/mL) (P =.005). Significant differences were also observed according to rs4149032 genotype: CC (LPV median Ctrough = 6027 ng/mL, IQR =4548–8250 ng/mL), CT (LPV median Ctrough = 5553 ng/mL, IQR = 4300–6888 ng/mL) and TT (LPV median Ctrough = 4408 ng/mL, IQR = 3361–5233 ng/mL) (P =.007). For rs4149056 a statistically significant difference between T‐homozygotes (LPV median Ctrough = 5434 ng/mL, IQR = 3855–6830 ng/mL), heterozygotes (LPV median Ctrough = 6707 ng/mL, IQR = 5088–8063 ng/mL) and C‐homozygotes (LPV median Ctrough = 13906 ng/mL, IQR = 12946–14866 ng/mL) was observed (P =.002). In multivariate regression analysis, only the SLCO1B1 rs4149056 polymorphism was independently associated with higher LPV Ctrough (β = 2834.5 [1442–4226.9] ng/mL [P =.001]). Conclusions: Our results demonstrate a statistically significant influence of the SLCO1B1 rs4149056 polymorphism on higher LPV Ctrough in Caucasian HIV/AIDS patients. [ABSTRACT FROM AUTHOR]

The aim of the study was to determine whether a correlation exists betweenMDR1 (ABCB1)gene polymorphisms at positions 3435 (C3435T) and 2677 (G2677T(A)) and the expression of human hepatic P-glycoprotein (P-gp).P-gp protein expression in 26 human livers was assessed by Western blotting andABCB1mRNA expression was determined by real time RT-PCR. The C3435T and G2677T(A) polymorphisms were identified by RFLP and direct sequence analysis, respectively.The C and G allele frequencies for the C3435T and G2677T(A) polymorphisms were 0.48 and 0.79, respectively, and the genotypes were in Hardy–Weinberg equilibrium. There was a 200- and 20-fold variation in the expression ofABCB1mRNA and Pgp protein expression, respectively. There were no differences in mRNA and protein expression identified amongst the different genotypes attributable to the C3435T and G2677T(A) polymorphisms in theABCB1gene. Exposure to a PXR ligand prior to death did not influence mRNA or protein expression.There is substantial variability in the expression of Pgp in human liver, but this is not due to the presence of C3435T and G2677T(A) polymorphisms in theABCB1gene, although our study is limited by a small sample size. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC 90 ., Methods: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC 90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials., Results: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated., Conclusion: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)