Increasing the bioavailability of oral esketamine by a single dose of cobicistat: A case study.

BACKGROUND: Intranasal esketamine is an approved drug for treatment­resistant depression (TRD); however, it is costly and may result in specific adverse effects. In this single case study, we explored if oral esketamine can be a suitable alternative. METHODS: In collaboration with a 39­year­old female with TRD, we compared plasma concentration curves of intranasal (84 mg) and oral (1, 2 and 4 mg/kg) esketamine. Because oral esketamine has a relatively low bioavailability, it results in a different ratio between esketamine and its primary metabolite noresketamine. To increase the bioavailability of oral esketamine, we co­administered a single dose of the cytochrome P­450 (CYP) 3A4 inhibitor cobicistat (150 mg). RESULTS: For all doses administered, oral esketamine resulted in lower esketamine but higher noresketamine peak plasma concentrations compared with intranasal treatment. Using oral esketamine it was not possible to generate a similar esketamine plasma concentration curve as with the intranasal treatment, except when combined with cobicistat (esketamine 2 mg/kg plus cobicistat 150 mg). CONCLUSIONS: Our findings demonstrate that cobicistat effectively increases the bioavailability of oral esketamine. Further research is required in a larger population, especially to investigate the clinical benefit of cobicistat as a booster drug for oral esketamine.

Pharmacokinetics of standard versus high-dose rifampin for tuberculosis preventive treatment: A sub-study of the 2R2 randomized controlled trial.

BACKGROUND: Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure. METHODS: A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R2 randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R20) and 30 mg/kg/day (2R30), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R10) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC0-24) and peak concentration (Cmax) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC0-24 and Cmax. RESULTS: We enrolled 51 participants in this study. In the 4R10, 2R20, and 2R30 arms, the geometric mean AUC0-24 was 68.0, 186.8, and 289.9 h⋅mg/L, and Cmax was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R10 arm, AUC0-24 and Cmax were significantly higher in the 2R20 and 2R30 arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC0-24 and Cmax (P < 0.05). AUC0-24 and Cmax values were much higher than those previously reported in persons with TB disease. CONCLUSIONS: Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.

Ten-year results of an international external quality control programme for measurement of anti-tuberculosis drug concentrations.

OBJECTIVES: Participation in an external (interlaboratory) quality control (QC) programme is an essential part of quality assurance as it provides laboratories with valuable insights into their analytical performance. We describe the 10 year results of an international QC programme for the measurement of anti-tuberculosis (TB) drugs. METHODS: Each year, two rounds were organized in which serum (or plasma) samples, spiked with known concentrations of anti-TB drugs, were provided to participating laboratories for analysis. Reported measurements within 80%-120% of weighed-in concentrations were considered accurate. Mixed model linear regression was performed to assess the effect of the measured drug, concentration level, analytical technique and performing laboratory on the absolute inaccuracy. RESULTS: By 2022, 31 laboratories had participated in the QC programme and 13 anti-TB drugs and metabolites were included. In total 1407 measurements were reported. First-line TB drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) represented 58% of all measurements. Overall, 83.2% of 1407 measurements were accurate, and the median absolute inaccuracy was 7.3% (IQR, 3.3%-15.1%). The absolute inaccuracy was related to the measured anti-TB drug and to the performing laboratory, but not to the concentration level or to the analytical technique used. The median absolute inaccuracies of rifampicin and isoniazid were relatively high (10.2% and 10.9%, respectively). CONCLUSIONS: The 10 year results of this external QC programme illustrate the need for continuous external QC for the measurement of anti-TB drugs for research and patient care purposes, because one in six measurements was inaccurate. Participation in the programme alerts laboratories to previously undetected analytical problems.

Influence of ultrafiltration conditions on the measurement of unbound drug concentrations: flucloxacillin as an example.

BACKGROUND: When performing therapeutic drug monitoring (TDM) for flucloxacillin, it is advised to measure the unbound, not the total, flucloxacillin concentration. To be able to accurately quantify unbound flucloxacillin concentrations, a reliable analytical method is indispensable. OBJECTIVE: To determine the influence of temperature and pH of the sample during ultrafiltration on the measured unbound fraction of flucloxacillin. MATERIALS AND METHODS: We performed three different experiments. In a single laboratory experiment, we investigated the influence of ultrafiltration temperature (10°C, room temperature and 37°C) on the measured unbound fraction of flucloxacillin for three concentration levels. In a multiple laboratory experiment, the results of eight laboratories participating in an international quality control programme measuring unbound flucloxacillin concentrations were analysed. In the third experiment, patient samples were ultrafiltrated using four different conditions: (i) physiological pH and room temperature; (ii) unadjusted pH (pH 9 after freezing) and room temperature; (iii) physiological pH and 37°C and (iv) unadjusted pH and 37°C. RESULTS: For all experiments, measurement of samples that were ultrafiltrated at room temperature resulted in a substantially lower unbound fraction compared to samples that were ultrafiltrated at 37°C. Adjusting the pH to physiological pH only had a minimal impact on the measured unbound fraction. CONCLUSIONS: On the basis of these findings and considering the need for fast, simple and reproducible sample pretreatment for TDM purposes, we conclude that ultrafiltration of flucloxacillin should be performed at physiological temperature (37°C), but adjustment of pH does not seem to be necessary.

Characteristics, knowledge, attitude, and practice of pharmacy personnel in supporting tuberculosis treatment: A multicenter cross-sectional study in a high-burden tuberculosis country.

BACKGROUND: Positive roles of community pharmacy in tuberculosis (TB) care have been widely reported. However, the actual practice of supporting TB treatment is not optimal yet. OBJECTIVES: We analyzed the current practice of community pharmacy personnel and its factors in supporting the successful treatment of TB patients in Indonesia, aiming to develop strategies for effective and sustainable TB practice models for the community pharmacy. METHODS: We performed a cross-sectional survey in 3 areas representing Indonesia's eastern, central, and western parts. Development and validation of the questionnaire were conducted to assess 4 domains, that is, characteristics, knowledge, attitudes, and practice of community pharmacy personnel in supporting the successful treatment of TB patients. Data were collected with purposive convenience sampling using online and offline questionnaires. Descriptive analyses were used to summarize factors in each domain, while binary logistic regression was used to analyze the associated factors of the practice. RESULTS: Thirty-five questionnaire items indicated a valid instrument, and the study successfully included 844 participants who comprised pharmacists (n = 473, 56%) and pharmacy assistants (n = 371, 44%). Although most of the knowledge items were correctly answered by more than 60% of the participants, items related to TB signs, risk groups, drug regimens, and medicine uses were still less than 60%. This was in line with exposure to updated TB training in only 51% of the participants (n = 426). Most of the participants had a positive attitude toward their professional role (n = 736, 87%), capability (n = 646, 77%), and consequences (n = 655, 78%) in supporting TB treatment. However, this was not aligned with the actual practice of supporting TB treatment, intensively performed by only 1.3% of participants (n = 11). We identified several factors associated with the practice, that is, a pharmacy assistant background (P < 0.05), short working time (P < 0.05), experience in TB training (P < 0.001), and a positive attitude (P < 0.001). CONCLUSION: This study highlighted a limited number of community pharmacy personnel intensively practicing as TB treatment supporters in Indonesia. An interventional package considering the identified factors is needed to develop effective and sustainable practices in the real world.

A genetic risk score to predict treatment nonresponse in psychotic depression.

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = -0.32, p = 0.0023, n = 88) and remission (r = -0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia.

BACKGROUND: Pharmacokinetic data on high-dose isoniazid for the treatment of rifampicin-/multidrug-resistant tuberculosis (RR/MDR-TB) are limited. We aimed to describe the pharmacokinetics of high-dose isoniazid, estimate exposure target attainment, identify predictors of exposures, and explore exposure-response relationships in RR/MDR-TB patients. METHODS: We performed an observational pharmacokinetic study, with exploratory pharmacokinetic/pharmacodynamic analyses, in Indonesian adults aged 18-65 years treated for pulmonary RR/MDR-TB with standardized regimens containing high-dose isoniazid (10-15 mg/kg/day) for 9-11 months. Intensive pharmacokinetic sampling was performed after ≥2 weeks of treatment. Total plasma drug exposure (AUC0-24) and peak concentration (Cmax) were assessed using non-compartmental analyses. AUC0-24/MIC ratio of 85 and Cmax/MIC ratio of 17.5 were used as exposure targets. Multivariable linear and logistic regression analyses were used to identify predictors of drug exposures and responses, respectively. RESULTS: We consecutively enrolled 40 patients (median age 37.5 years). The geometric mean isoniazid AUC0-24 and Cmax were 35.4 h·mg/L and 8.5 mg/L, respectively. Lower AUC0-24 and Cmax values were associated (P < 0.05) with non-slow acetylator phenotype, and lower Cmax values were associated with male sex. Of the 26 patients with MIC data, less than 25% achieved the proposed targets for isoniazid AUC0-24/MIC (n = 6/26) and Cmax/MIC (n = 5/26). Lower isoniazid AUC0-24 values were associated with delayed sputum culture conversion (>2 months of treatment) [adjusted OR 0.18 (95% CI 0.04-0.89)]. CONCLUSIONS: Isoniazid exposures below targets were observed in most patients, and certain risk groups for low isoniazid exposures may require dose adjustment. The effect of low isoniazid exposures on delayed culture conversion deserves attention.

Clofazimine as a substitute for rifampicin improves efficacy of Mycobacterium avium pulmonary disease treatment in the hollow-fiber model.

Mycobacterium avium complex pulmonary disease is treated with an azithromycin, ethambutol, and rifampicin regimen, with limited efficacy. The role of rifampicin is controversial due to inactivity, adverse effects, and drug interactions. Here, we evaluated the efficacy of clofazimine as a substitute for rifampicin in an intracellular hollow-fiber infection model. THP-1 cells, which are monocytes isolated from peripheral blood from an acute monocytic leukemia patient, were infected with M. avium ATCC 700898 and exposed to a regimen of azithromycin and ethambutol with either rifampicin or clofazimine. Intrapulmonary pharmacokinetic profiles of azithromycin, ethambutol, and rifampicin were simulated. For clofazimine, a steady-state average concentration was targeted. Drug concentrations and bacterial densities were monitored over 21 days. Exposures to azithromycin and ethambutol were 20%-40% lower than targeted but within clinically observed ranges. Clofazimine exposures were 1.7 times higher than targeted. Until day 7, both regimens were able to maintain stasis. Thereafter, regrowth was observed for the rifampicin-containing regimen, while the clofazimine-containing regimen yielded a 2 Log10 colony forming unit (CFU) per mL decrease in bacterial load. The clofazimine regimen also successfully suppressed the emergence of macrolide tolerance. In summary, substitution of rifampicin with clofazimine in the hollow-fiber model improved the antimycobacterial activity of the regimen. Clofazimine-containing regimens merit investigation in clinical trials.

Isoniazid exposures and acetylator status in Indonesian tuberculous meningitis patients.

The effect of acetylator status on the exposure to isoniazid in plasma and CSF in tuberculous meningitis (TBM) patients remains largely unexplored. Here, we describe isoniazid exposures and acetylator status of 48 subjects in the ReDEFINe study (NCT02169882). Fifty percentwere fast (half-life <130 min) or slow (half-life >130 min) acetylators. Slow acetylators had higher AUC0-24, Cmax and CSF concentrations than fast acetylators (GM AUC0-24 25.5 vs 10.6 mg/L*h, p < 0.001); plasma Cmax 5.5 vs 3.6 mg/L, p = 0.023; CSF concentration 1.9 vs 1.1 mg/L, p = 0.008). Higher isoniazid doses may benefit fast acetylators in TBM.

Power to identify exposure-response relationships in phase IIa pulmonary tuberculosis trials with multi-dimensional bacterial load modeling.

Adequate power to identify an exposure-response relationship in a phase IIa clinical trial for pulmonary tuberculosis (TB) is important for dose selection and design of follow-up studies. Currently, it is not known what response marker provides the pharmacokinetic-pharmacodynamic (PK-PD) model more power to identify an exposure-response relationship. We simulated colony-forming units (CFU) and time-to-positivity (TTP) measurements for four hypothetical drugs with different activity profiles for 14 days. The power to identify exposure-response relationships when analyzing CFU, TTP, or combined CFU + TTP data was determined at 60 total participants, or with 25 out of 60 participants in the lowest and highest dosing groups (unbalanced design). For drugs with moderate bactericidal activity, power was low (<59%), irrespective of the data analyzed. Power was 1.9% to 29.4% higher when analyzing TTP data compared to CFU data. Combined analysis of CFU and TTP further improved the power, on average by 4.2%. For a drug with a medium-high activity, the total sample size needed to achieve 80% power was 136 for CFU, 72 for TTP, and 68 for combined CFU + TTP data. The unbalanced design improved the power by 16% over the balanced design. In conclusion, the power to identify an exposure-response relationship is low for TB drugs with moderate bactericidal activity or with a slow onset of activity. TTP provides the PK-PD model with more power to identify exposure-response relationships compared to CFU, and combined analysis or an unbalanced dosing group study design offers modest further improvement.

Clofazimine Is a Safe and Effective Alternative for Rifampicin in Mycobacterium avium Complex Pulmonary Disease Treatment: Outcomes of a Randomized Trial.

BACKGROUND: Results of retrospective studies have suggested clofazimine as an alternative for rifampicin in the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). RESEARCH QUESTION: Is a treatment regimen consisting of clofazimine-ethambutol-macrolide noninferior to the standard treatment regimen (rifampicin-ethambutol-macrolide) in the treatment of MAC-PD? STUDY DESIGN AND METHODS: In this single-center, nonblinded clinical trial, adult patients with MAC-PD were randomly assigned in a 1:1 ratio to receive rifampicin or clofazimine as adjuncts to an ethambutol-macrolide regimen. The primary outcome was sputum culture conversion following 6 months of treatment. RESULTS: Forty patients were assigned to receive either rifampicin (n = 19) or clofazimine (n = 21) in addition to ethambutol and a macrolide. Following 6 months of treatment, both arms showed similar percentages of sputum culture conversion based on an intention-to-treat analysis: 58% (11 of 19) for rifampicin and 62% (13 of 21) for clofazimine. Study discontinuation, mainly due to adverse events, was equal in both arms (26% vs 33%). Based on an on-treatment analysis, sputum culture conversion following 6 months of treatment was 79% in both groups. In the clofazimine arm, diarrhea was more prevalent (76% vs 37%; P = .012), while arthralgia was more frequent in the rifampicin arm (37% vs 5%; P = .011). No difference in the frequency of QTc prolongation was seen between groups. INTERPRETATION: A clofazimine-ethambutol-macrolide regimen showed similar results to the standard rifampicin-ethambutol-macrolide regimen and should be considered in the treatment of MAC-PD. The frequency of adverse events was similar in both arms, but their nature was different. Individual patient characteristics and possible drug-drug interactions should be taken into consideration when choosing an antibiotic regimen for MAC-PD. CLINICAL TRIAL REGISTRATION: EudraCT; No.: 2015-003786-28; URL: https://eudract.ema.europa.eu.

A Single-Run HPLC-MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis.

The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography-mass spectrometry (HPLC-MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20-25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.

Successful addition of topical antibiotic treatment after surgery in treatment-refractory nontuberculous mycobacterial skin and soft tissue infections.

Treatment of skin and soft tissue infections with nontuberculous mycobacteria sometimes fails despite repeated debridements and long-term systemic antibiotic therapy. These treatment-refractory infections can cause significant morbidity and pose a treatment challenge. Following surgery, we treated three patients with negative pressure wound therapy with the instillation and dwell time of topical antibiotics, in addition to systemic antibiotic treatment. Treatment was successful and well tolerated, except for some local irritation.

Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.

BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. METHODS AND FINDINGS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. TRIAL REGISTRATION: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

The role of rifampicin within the treatment of Mycobacterium avium pulmonary disease.

Rifampicin is recommended for the treatment of Mycobacterium avium complex pulmonary disease alongside azithromycin and ethambutol. We evaluated the azithromycin-ethambutol backbone with and without rifampicin in an intracellular hollow fiber model and performed RNA sequencing to study the differences in adaptation. In an in vitro hollow fiber experiment, we simulated epithelial lining fluid pharmacokinetic profiles of the recommended 3-drug (rifampicin, ethambutol, and azithromycin) or a 2-drug (ethambutol and azithromycin) treatment. THP-1 cells infected with M. avium ATCC700898 were exposed to these regimens for 21 days. We determined intra- and extra-cellular bacterial load- and THP-1 cell densities on days 0, 3, 7, 14, and 21, alongside RNA sequencing. The emergence of macrolide resistance was studied by inoculating intra- and extra-cellular fractions of azithromycin-containing Middlebrook 7H10 agar plates. Complete pharmacokinetic profiles were determined at days 0 and 21. Both therapies maintained stasis of both intra- and extra-cellular bacterial populations for 3 days, whilst regrowth coinciding with the emergence of a macrolide-resistant subpopulation was seen after 7 days. THP-1 cell density remained static. Similar transcriptional profiles were observed for both therapies that were minimally influenced by exposure duration. Transcriptional response was slightly larger during 2-drug treatment. Rifampicin did not add to the antimycobacterial effect to the 2-drug therapy or suppression of emergence resistance. RNA transcription was not greatly altered by the addition of rifampicin, which may be due to strong transcriptional influence of azithromycin and host cells. This questions the role of rifampicin in the currently recommended therapy. These findings should be confirmed in clinical trials.

First-Line Antituberculosis Drug Concentrations in Infants With HIV and a History of Recent Admission With Severe Pneumonia.

Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants.

Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin.

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin.

Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of UGT1A1, a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7-36.7) and 153 (138-175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h-1, and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1-1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of UGT1A1 did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen.

Developing contents for a digital adherence tool: A formative mixed-methods study among children and adolescents living with HIV in Tanzania.

Optimal adherence (>95%) to antiretroviral treatment (ART) remains a challenge among children and adolescents living with HIV (CALHIV). Digital adherence tools (DAT) with reminder cues have proven feasible among adult people living with HIV (PLHIV), with some concerns about the risk of HIV status disclosure. We aimed to assess the needs, contents and acceptability of an SMS-based DAT among CALHIV. We first conducted a survey to understand potential barriers to using DAT among CALHIV, then tested the DAT intervention among purposively selected participants. The DAT intervention included using the Wisepill device, receiving daily reminder SMS and receiving adherence reports on how they had taken medication in the past month. The content of the reminder SMS differed over time from asking if the medication was taken to a more neutral SMS like "take care". Afterwards, we conducted exit interviews, in-depth interviews, and focus-group discussions. We analysed quantitative findings descriptively and used thematic content analysis for qualitative data. We included 142 children and 142 adolescents in the survey, and 20 of each used the intervention. Eighty-five percent (121/142) of surveyed participants indicated they would like to receive reminder SMS. Most of them (97/121-80%) of children and 94/121(78%) of adolescents would prefer to receive daily reminders. Participants who used the DAT mentioned to be happy to use the device. Ninety percent of them had good experience with receiving reminders and agreed that the SMS made them take medication. However, 25% experienced network problems. Participants preferred neutral reminder SMSs that did not mention the word 'medication', but preserved confidentiality. The provided adherence reports inspired participants to improve their adherence. None of the participants experienced unwanted disclosure or stigmatisation due to DAT. However, 5% of adolescents were concerned about being monitored daily. This study showed that DAT is acceptable and provided insight of the needed SMS content for a customized DAT for CALHIV.