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1.
AIDS Res Ther ; 21(1): 34, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773606

RESUMO

INTRODUCTION: Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited. METHODS: A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose. RESULTS: Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR. CONCLUSIONS: In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.


Assuntos
Adenina , Alanina , Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Falência Renal Crônica , Oxazinas , Diálise Peritoneal , Piperazinas , Piridonas , Tenofovir , Humanos , Masculino , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/farmacocinética , Piridonas/farmacocinética , Pessoa de Meia-Idade , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Emtricitabina/farmacocinética , Emtricitabina/uso terapêutico , Piperazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Alanina/farmacocinética , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapêutico , Falência Renal Crônica/terapia
2.
Ther Drug Monit ; 46(3): 277-280, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38723113

RESUMO

BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.


Assuntos
Carbamazepina , Darunavir , Interações Medicamentosas , Infecções por HIV , Humanos , Darunavir/uso terapêutico , Darunavir/farmacocinética , Masculino , Pessoa de Meia-Idade , Carbamazepina/uso terapêutico , Carbamazepina/farmacocinética , Infecções por HIV/tratamento farmacológico , Neuralgia do Trigêmeo/tratamento farmacológico , Ritonavir/uso terapêutico , Ritonavir/administração & dosagem , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/administração & dosagem , Piridonas/farmacocinética , Piridonas/uso terapêutico , Piridonas/sangue , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/farmacocinética , Oxazinas/uso terapêutico , Oxazinas/farmacocinética , Relação Dose-Resposta a Droga , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Monitoramento de Medicamentos/métodos
3.
Antimicrob Agents Chemother ; 68(5): e0150423, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38587380

RESUMO

A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h-1, respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h-1. The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Humanos , Lamivudina/farmacocinética , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Oxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Piperazinas/farmacocinética , Piridonas/farmacocinética , Adulto , Masculino , Feminino , HIV-1/efeitos dos fármacos , Pessoa de Meia-Idade , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Combinação de Medicamentos
4.
Clin Pharmacokinet ; 63(5): 721-728, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38573477

RESUMO

BACKGROUND AND OBJECTIVE: Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together. METHODS: Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (Cmax) of each compound were within 0.70-1.43, we considered this as no clinically relevant PK interaction. RESULTS: A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0-∞ and Cmax fell outside our acceptance criteria of 0.70-1.43. CONCLUSIONS: Although TAF AUC and Cmax 90% CIs fell outside the pre-defined criteria (0.62-1.11 and 0.65-1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.


Assuntos
Alanina , Disponibilidade Biológica , Emtricitabina , Voluntários Saudáveis , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Comprimidos , Tenofovir , Humanos , Piridonas/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/sangue , Tenofovir/farmacocinética , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Masculino , Emtricitabina/farmacocinética , Emtricitabina/administração & dosagem , Piperazinas/farmacocinética , Feminino , Adulto , Oxazinas/farmacocinética , Oxazinas/administração & dosagem , Alanina/farmacocinética , Alanina/administração & dosagem , Combinação de Medicamentos , Adulto Jovem , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/administração & dosagem , Adenina/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Área Sob a Curva , Pessoa de Meia-Idade , Adolescente , Estudos Cross-Over
5.
J Acquir Immune Defic Syndr ; 96(1): 85-91, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38372621

RESUMO

BACKGROUND: Dolutegravir exposure is reduced after switching from efavirenz, which could select for dolutegravir resistance if switching occurs during virologic failure. METHODS: We measured serial dolutegravir trough concentrations after switching from efavirenz in a clinical trial, which randomized some participants to a supplemental dolutegravir dose or placebo for the first 14 days. Changes in dolutegravir trough concentrations between days 3, 7, 14, and 28 were evaluated. The primary outcome was the geometric mean ratio of dolutegravir trough concentrations on day 7 versus day 28. RESULTS: Twenty-four participants received double-dose dolutegravir (50 mg twice daily) and 11 standard dose for the first 14 days. Baseline characteristics were 77% female, median age 36 years, CD4 cell count 254 cells/mm3, and HIV-1 RNA 4.0 log10 copies/mL. The geometric mean ratio (90% CI) of dolutegravir trough concentrations on day 7 versus day 28 was 0.637 (0.485 to 0.837) in the standard-dose group and 1.654 (1.404 to 1.948) in the double-dose group. There was a prolonged induction effect at day 28 in participants with efavirenz slow metaboliser genotypes. One participant in the double-dose group had a dolutegravir trough concentration below the protein-binding adjusted concentration needed to inhibit 90% of HIV-1 (PA-IC90) at day 3. CONCLUSIONS: No participants on standard-dose dolutegravir had dolutegravir trough concentrations below the PA-IC90. Slow efavirenz metaboliser genotypes had higher baseline efavirenz concentrations and more pronounced and longer period of induction postswitch. These findings suggest that a 14-day lead-in supplemental dolutegravir dose may not be necessary when switching from a failing efavirenz-based first-line regimen.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adulto , Feminino , Humanos , Masculino , Alcinos/farmacocinética , Alcinos/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/farmacocinética , Benzoxazinas/uso terapêutico , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Infecções por HIV/tratamento farmacológico , Oxazinas/farmacocinética , Oxazinas/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Piridonas/farmacocinética , Piridonas/uso terapêutico
6.
Br J Clin Pharmacol ; 90(5): 1247-1257, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38332460

RESUMO

AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.


Assuntos
Creatinina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Humanos , Piridonas/farmacocinética , Oxazinas/farmacocinética , Oxazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Masculino , Creatinina/sangue , Feminino , Infecções por HIV/tratamento farmacológico , Adulto , África do Sul , Pessoa de Meia-Idade , Glucuronosiltransferase/genética , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , HIV-1/genética , HIV-1/efeitos dos fármacos , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Inibidores de Integrase de HIV/efeitos adversos , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Emtricitabina/uso terapêutico , Emtricitabina/farmacocinética , Polimorfismo de Nucleotídeo Único
7.
Clin Pharmacokinet ; 61(7): 955-972, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35781630

RESUMO

Fostamatinib is the first approved spleen tyrosine kinase inhibitor for chronic immune thrombocytopenia. This review summarizes the clinical development, pharmacokinetics, pharmacodynamics, drug-drug interactions, adverse events, and comprehensive analyses of fostamatinib. While integrating these findings, we discuss the fostering and improvement of fostamatinib for further clinical applications. Fostamatinib is designed as a prodrug and cleavage of its active moiety R406 in the intestine. As R406 is the major product in the blood, this review mainly discusses the pharmacokinetics and pharmacodynamics of R406. It is metabolized by cytochrome 3A4 and UGT1A9 in the liver and is dominantly excreted in feces after anaerobic modification by the gut microbiota. As fostamatinib and R406 strongly inhibit the breast cancer resistance protein, the interaction with those substrates, particularly statins, should be carefully monitored. In patients with immune thrombocytopenia, fostamatinib administration started at 100 mg twice daily, and most patients increased to 150 mg twice daily in the clinical trial. Although responders showed a higher R406 concentration than non-responders, the correlation between R406 exposure and achievement of the platelet count as a pharmacodynamic marker was uncertain in the pharmacokinetic/pharmacodynamic analysis. Additionally, R406 concentration was almost halved in patients with a heavy body weight; hence, the exposure-efficacy study for suitable dosing should be continued with post-marketing data. In contrast, the pharmacokinetic/pharmacodynamic analysis for exposure safety revealed that R406 exposure significantly correlated with the incidence of hypertension. Even though the influence of elevated exposure on other toxicities, including diarrhea and neutropenia, is still unclear, careful management is required with dose escalation to avoid toxicity-related discontinuation.


Assuntos
Púrpura Trombocitopênica Idiopática , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Aminopiridinas , Humanos , Morfolinas , Proteínas de Neoplasias , Oxazinas/farmacocinética , Piridinas/farmacocinética , Pirimidinas
8.
Antimicrob Agents Chemother ; 66(6): e0021522, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35604212

RESUMO

Dolutegravir-based regimens are recommended as first-line therapy for HIV in low- and middle-income countries where tuberculosis is the most common opportunistic infection. Concurrent HIV/tuberculosis treatment is challenging because of drug-drug interactions. Our analysis aimed to characterize dolutegravir's population pharmacokinetics when coadministered with rifampicin and assess alternative dolutegravir dosing regimens. We developed a population pharmacokinetic model of dolutegravir in NONMEM with data from two healthy-volunteer studies (RADIO and ClinicalTrials.gov identifier NCT01231542) and validated it with data from the INSPIRING study, which consisted of participants living with HIV. The model was developed with 817 dolutegravir plasma concentrations from 41 participants. A 2-compartment model with first-order elimination and lagged absorption best described dolutegravir's pharmacokinetics. For a typical 70-kg individual, we estimated a clearance, absorption rate constant, central volume, and peripheral volume of 1.03 L/h, 1.61 h-1, 12.7 L, and 3.85 L, respectively. Rifampicin coadministration increased dolutegravir clearance by 144% (95% confidence interval [CI], 126 to 161%). Simulations showed that when 50 or 100 mg once-daily dolutegravir is coadministered with rifampicin in 70-kg individuals, 71.7% and 91.5% attain trough concentrations above 0.064 mg/L, the protein-adjusted 90% inhibitory concentration (PA-IC90), respectively. The model developed from healthy-volunteer data describes patient data reasonably well but underpredicts trough concentrations. Although 50 mg of dolutegravir given twice daily achieves target concentrations in more than 99% of individuals cotreated with rifampicin, 100 mg of dolutegravir, once daily, in the same population is predicted to achieve satisfactory pharmacokinetic target attainment. The efficacy of this regimen should be investigated since it presents an opportunity for treatment simplification.


Assuntos
Infecções por HIV , Tuberculose , Estudos Clínicos como Assunto , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Oxazinas/farmacocinética , Piperazinas , Piridonas/uso terapêutico , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico
9.
Br J Clin Pharmacol ; 88(9): 4230-4236, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35524344

RESUMO

XBD173 and etifoxine are translocator protein (TSPO) ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the Ki for etifoxine in human brain derived here (7.8 µM, 95% CI 4.5-14.6 µM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily.


Assuntos
Purinas , Receptores de GABA , Proteínas de Transporte/metabolismo , Humanos , Oxazinas/farmacocinética , Purinas/farmacologia , Receptores de GABA/metabolismo
10.
Molecules ; 27(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35164134

RESUMO

The red imported fire ant (Solenopsis invicta) is one of the deadliest invasive ant species that threatens the world by disrupting biodiversity, important functions within a natural ecosystem, and community structure. They are responsible for huge economic losses in the infested countries every year. Synthetic insecticides, especially indoxacarb, have been broadly used to control S. invicta for many years. However, the biochemical response of S. invicta to indoxacarb remains largely undiscovered. Here, we used the sublethal doses of indoxacarb on the S. invicta collected from the eight different cities of Southern China. The alteration in the transcriptome profile of S. invicta following sublethal dosages of indoxacarb was characterized using high-throughput RNA-seq technology. We created 2 libraries, with 50.93 million and 47.44 million clean reads for indoxacarb treatment and control, respectively. A total of 2018 unigenes were regulated after insecticide treatment. Results indicated that a total of 158 differentially expressed genes (DEGs) were identified in the indoxacarb-treated group, of which 100 were significantly upregulated and 58 were downregulated, mostly belonging to the detoxification enzymes, such as AChE, CarE, and GSTs. Furthermore, results showed that most of these DEGs were found in several KEGG pathways, including steroid biosynthesis, other drug metabolizing enzymes, glycerolipid metabolism, chemical carcinogenesis, drug-metabolizing cytochrome P450, glutathione metabolism, glycerophospholipid metabolism, glycolysis/gluconeogenesis, and metabolism of xenobiotics. Together, these findings indicated that indoxacarb causes significant alteration in the transcriptome profile and signaling pathways of S. invicta, providing a foundation for further molecular inquiry.


Assuntos
Formigas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteínas de Insetos , Espécies Introduzidas , Oxazinas , RNA-Seq , Animais , Formigas/enzimologia , Formigas/genética , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Oxazinas/farmacocinética , Oxazinas/farmacologia
11.
Neurosci Lett ; 771: 136463, 2022 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-35051435

RESUMO

Social factors are associated with psychiatric outcomes and brain function. Relationships between local population data obtained from Social Explorer analyses of the American Community Survey (2014-2018) and dopamine D2/3 receptor (D2/3R) availability were explored in this retrospective analysis of [11C]PHNO positron emission tomography (PET) imaging data (n = 70). Larger local population size and lower percentage of the population with a bachelor's degree or higher were significantly associated with higher striatal D2/3R availability, suggesting that living in a populous area with fewer educational resources may be accompanied by stressors with concomitant dopaminergic changes. Future prospective, collaborative studies are needed to better understand the precise etiology of the observed relationships.


Assuntos
Encéfalo/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Meio Social , Adulto , Encéfalo/diagnóstico por imagem , Agonistas de Dopamina/farmacocinética , Feminino , Humanos , Masculino , Oxazinas/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Status Social
12.
Pediatr Infect Dis J ; 41(2): 131-132, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35017453
13.
Pediatr Infect Dis J ; 41(3): 230-237, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34817414

RESUMO

BACKGROUND: The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS: The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS: As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS: These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Didesoxinucleosídeos , Combinação de Medicamentos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Lamivudina , Pessoa de Meia-Idade , Oxazinas/farmacocinética , Piperazinas/farmacocinética , Piridonas/farmacocinética , Comprimidos/administração & dosagem , Adulto Jovem
14.
J Med Chem ; 64(18): 13572-13587, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34496560

RESUMO

Ribosomal S6 protein kinase 4 (RSK4) was identified to be a promising target for the treatment of esophageal squamous cell carcinoma (ESCC) in our previous research, whose current treatments are primarily chemotherapy and radiotherapy due to the lack of targeted therapy. However, few potent and specific RSK4 inhibitors are reported. In this study, a series of 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones derivatives were designed and synthesized as novel and potent RSK4 inhibitors. Compound 14f was identified with potent RSK4 inhibitory activity both in vitro and in vivo. 14f significantly inhibited the proliferation and invasion of ESCC cells in vitro with IC50 values of 0.57 and 0.98 µM, respectively. It dose dependently inhibited the phosphorylation of RSK4 downstream substrates while exerting little effect on the substrates of RSK1-3 in ESCC cells. The markedly suppressed tumor growth and no observed toxicity to main organs in the ESCC xenograft mouse model suggested 14f to be a promising RSK4-targeting agent for ESCC treatment.


Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Oxazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/metabolismo , Oxazinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 90-kDa/química , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Pharmacogenomics ; 22(15): 963-972, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34528449

RESUMO

Aim: Despite the high disease burden of human immunodeficiency virus (HIV) infection and colorectal cancer (CRC) in South Africa (SA), treatment-relevant pharmacogenetic variants are understudied. Materials & methods: Using publicly available genotype and gene expression data, a bioinformatic pipeline was developed to identify liver expression quantitative trait loci (eQTLs). Results: A novel cis-eQTL, rs28967009, was identified for UGT1A1, which is predicted to upregulate UGT1A1 expression thereby potentially affecting the metabolism of dolutegravir and irinotecan, which are extensively prescribed in SA for HIV and colorectal cancer treatment, respectively. Conclusion: As increased UGT1A1 expression could affect the clinical outcome of dolutegravir and irinotecan treatment by increasing drug clearance, patients with the rs28967009A variant may require increased drug doses to reach therapeutic levels or should be prescribed alternative drugs.


Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Glucuronosiltransferase/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Antineoplásicos Fitogênicos , Biologia Computacional , Genótipo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Irinotecano/farmacocinética , Irinotecano/uso terapêutico , Fígado/enzimologia , Oxazinas/farmacocinética , Oxazinas/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Piridonas/farmacocinética , Piridonas/uso terapêutico , Controle de Qualidade , África do Sul , Resultado do Tratamento , Regulação para Cima
16.
Mol Neurobiol ; 58(11): 5703-5721, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34390469

RESUMO

Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme's catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.


Assuntos
Antirretrovirais/toxicidade , Compostos Heterocíclicos com 3 Anéis/toxicidade , Inibidores de Metaloproteinases de Matriz/toxicidade , Defeitos do Tubo Neural/induzido quimicamente , Transtornos do Neurodesenvolvimento/induzido quimicamente , Doenças Neuroinflamatórias/induzido quimicamente , Oxazinas/toxicidade , Piperazinas/toxicidade , Piridonas/toxicidade , Animais , Antirretrovirais/farmacocinética , Antirretrovirais/farmacologia , Encéfalo/embriologia , Encéfalo/enzimologia , Domínio Catalítico/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Masculino , Inibidores de Metaloproteinases de Matriz/farmacocinética , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Simulação de Acoplamento Molecular , Defeitos do Tubo Neural/embriologia , Neuroimagem , Doenças Neuroinflamatórias/embriologia , Oxazinas/farmacocinética , Oxazinas/farmacologia , Piperazinas/farmacocinética , Piperazinas/farmacologia , Placenta/química , Gravidez , Piridonas/farmacocinética , Piridonas/farmacologia , Distribuição Tecidual , Zinco/metabolismo
17.
Molecules ; 26(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361816

RESUMO

Fostamatinib is a prodrug of the active metabolite tamatinib, which is a spleen tyrosine kinase (Syk) inhibitor used in the treatment of primary chronic adult immune thrombocytopenia and rheumatoid arthritis. A highly sensitive, rapid, reliable, and green method was developed and validated using ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS) for quantification of tamatinib in rat plasma. Ibrutinib was used as internal standard and liquid-liquid extraction was applied using tert-butyl methyl ether. The analyte was separated on an AcquityTM CSH C18 (2.1 mm × 100 mm, 1.7 µm) column using mobile phase consisting of 10 mM ammonium acetate and acetonitrile (10:90) and the flow rate was 0.25 mL/min. Electrospray ionization (ESI) was carried out in positive mode. Quantitation of tamatinib and the IS was performed using multiple reaction monitoring mode with precursor-to-product transitions of m/z 471.1 > 122.0 and m/z 441.1 > 84.0, respectively. The calibration range was 0.1-1000.0 ng/mL and the linearity of the method was ≥0.997. The developed method greenness was investigated. All principal parameters for the method, including linearity, accuracy, precision, recovery, and stability, were within acceptable ranges. Tamatinib pharmacokinetic study in rats was successfully carried out using the developed method.


Assuntos
Inibidores Enzimáticos/farmacocinética , Oxazinas/farmacocinética , Pirazóis/química , Piridinas/farmacocinética , Quinase Syk/antagonistas & inibidores , Aminopiridinas , Animais , Cromatografia Líquida , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Extração Líquido-Líquido , Morfolinas , Oxazinas/sangue , Oxazinas/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacocinética , Piridinas/sangue , Piridinas/metabolismo , Pirimidinas , Ratos , Quinase Syk/química , Espectrometria de Massas em Tandem
18.
Clin Pharmacol Drug Dev ; 10(9): 985-993, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34265164

RESUMO

Pharmacokinetics, safety, and tolerability of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg were assessed in this phase 1, single-arm, open-label, single-dose study in fasted healthy male (n = 4) and female (n = 8) participants of Japanese heritage. Participants received a single dose of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg after an 8-hour fast, with safety assessments and blood samples for pharmacokinetic parameters collected through 72 hours after dosing. Geometric mean maximum plasma concentrations were 5.22 µg/mL (time to maximum concentration [tmax ], 1.01 hours) for abacavir, 4.13 µg/mL (tmax , 3.50 hours) for dolutegravir, and 3.35 µg/mL (tmax , 2.98 hours) for lamivudine. Geometric mean area under the concentration-time curve values were 18.20, 71.60, and 16.60 µg • h/mL for abacavir, dolutegravir, and lamivudine, respectively. No adverse events were reported, and no clinically significant findings were observed in laboratory values, physical examinations, or 12-lead electrocardiographic parameters. Single-tablet administration of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg was well tolerated in Japanese participants. Exposure to abacavir and lamivudine was comparable with that seen in previous studies. A modest increase in exposure to dolutegravir vs previous clinical studies was observed but is not expected to impact the clinical management of HIV-1 or increase the risk for adverse events.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Didesoxinucleosídeos/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Lamivudina/administração & dosagem , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Administração Oral , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Povo Asiático , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/farmacocinética , Combinação de Medicamentos , Feminino , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Lamivudina/efeitos adversos , Lamivudina/farmacocinética , Masculino , Pessoa de Meia-Idade , Oxazinas/efeitos adversos , Oxazinas/farmacocinética , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Piridonas/efeitos adversos , Piridonas/farmacocinética , Comprimidos , Adulto Jovem
19.
J Acquir Immune Defic Syndr ; 87(4): 1072-1078, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34153013

RESUMO

BACKGROUND: Virological failure during antiretroviral treatment (ART) may indicate the presence of drug resistance, but may also originate from nonadherence. Qualitative detection of ART components using drug level testing may be used to differentiate between these scenarios. We aimed to validate and implement qualitative point-of-care drug level tests for efavirenz (EFV), lopinavir (LPV), and dolutegravir (DTG) in rural South Africa. METHODS: Qualitative performance of immunoassays for EFV, LPV, and DTG was assessed by calculating limit of detection (LoD), region of uncertainty, and qualitative agreement with a reference test. Minimum duration of nonadherence resulting in a negative drug level test was assessed by simulation of treatment cessation using validated population pharmacokinetic models. RESULTS: LoD was 0.05 mg/L for EFV, 0.06 mg/L for LPV, and 0.02 mg/L for DTG. Region of uncertainty was 0.01-0.06 mg/L for EFV, 0.01-0.07 mg/L for LPV, and 0.01-0.02 mg/L for DTG. Qualitative agreement with reference testing at the LoD in patient samples was 95.2% (79/83) for EFV, 99.3% (140/141) for LPV, and 100% (118/118) for DTG. After simulated treatment cessation, median time to undetectability below LoD was 7 days [interquartile range (IQR) 4-13] for EFV, 30 hours (IQR 24-36) for LPV, and 6 days (IQR 4-7) for DTG. CONCLUSIONS: We demonstrate that qualitative ART drug level testing using immunoassays is feasible in a rural resource-limited setting. Implementation of this technology enables reliable detection of recent nonadherence and may allow for rapid and cost-effective differentiation between patients in need for adherence counseling and patients who require drug resistance testing or alternative treatment.


Assuntos
Alcinos/administração & dosagem , Fármacos Anti-HIV/sangue , Benzoxazinas/administração & dosagem , Ciclopropanos/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Lopinavir/administração & dosagem , Adesão à Medicação , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Testes Imediatos/normas , Piridonas/administração & dosagem , Alcinos/farmacocinética , Alcinos/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/farmacocinética , Benzoxazinas/uso terapêutico , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1 , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Técnicas Imunoenzimáticas/métodos , Limite de Detecção , Lopinavir/farmacocinética , Lopinavir/uso terapêutico , Oxazinas/farmacocinética , Oxazinas/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Testes Imediatos/economia , Piridonas/farmacocinética , Piridonas/uso terapêutico , Reprodutibilidade dos Testes , População Rural , África do Sul
20.
AAPS PharmSciTech ; 22(3): 127, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33835317

RESUMO

Being a candidate of BCS class II, dolutegravir (DTG), a recently approved antiretroviral drug, possesses solubility issues. The current research was aimed to improve the solubility of the DTG and thereby enhance its efficacy using the solid dispersion technique. In due course, the miscibility study of the drug was performed with different polymers, where Poloxamer 407 (P407) was found suitable to move forward. The solid dispersion of DTG and P407 was formulated using solvent evaporation technique with a 1:1 proportion of drug and polymer, where the solid-state characterization was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray diffraction. No physicochemical interaction was found between the DTG and P407 in the fabricated solid dispersion; however, crystalline state of the drug was changed to amorphous as evident from the X-ray diffractogram. A rapid release of DTG was observed from the solid dispersion (>95%), which is highly significant (p<0.05) as compared to pure drug (11.40%), physical mixture (20.07%) and marketed preparation of DTG (35.30%). The drug release from the formulated solid dispersion followed Weibull model kinetics. Finally, the rapid drug release from the solid dispersion formulation revealed increased Cmax (14.56 µg/mL) when compared to the physical mixture (4.12 µg/mL) and pure drug (3.45 µg/mL). This was further reflected by improved bioavailability of DTG (AUC: 105.99±10.07 µg/h/mL) in the experimental Wistar rats when compared to the AUC of animals administered with physical mixture (54.45±6.58 µg/h/mL) and pure drug (49.27±6.16 µg/h/mL). Therefore, it could be concluded that the dissolution profile and simultaneously the bioavailability of DTG could be enhanced by means of the solid dispersion platform using the hydrophilic polymer, P407, which could be projected towards improved efficacy of the drug in HIV/AIDS.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Oxazinas/administração & dosagem , Oxazinas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Animais , Fármacos Anti-HIV/uso terapêutico , Área Sob a Curva , Disponibilidade Biológica , Composição de Medicamentos , Liberação Controlada de Fármacos , Excipientes , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Masculino , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Poloxâmero , Piridonas/uso terapêutico , Ratos , Ratos Wistar , Solubilidade , Difração de Raios X
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