Adverse Outcomes in Pulmonary Tuberculosis patients on Retreatment Regimen: Evaluation of Pharmacokinetic Estimates as Risk Indicators

Patients with pulmonary tuberculosis (PTB) who fail therapy or develop a relapse are initiated on re-treatment regimen. These patients are known to have adverse outcomes. This study aimed to determine the role of plasma levels of Anti-tubercular drugs in treatment outcome. Plasma levels of retreatment regimen drugs [Isoniazid(INH), Rifampicin(RIF), Pyrazinamide(PZA), Ethambutol(EMB), and Streptomycin(STM)] were compared between treatment responsive/cured and treatment failure/not-cured patients. Plasma drug levels were analysed by LC-MS/MS at different time points in 134 PTB patients on retreatment regimen. Of the 134 subjects, 108 were cured, 17 patients developed multi-drug resistant TB (MDR-TB), and 9 patients remained smear positive at treatment completion (8 months). The two-hour plasma levels (C2hr) (geometric mean) were lower in 'Not Cured' subjects compared to 'Cured' subjects Notably, in the 26 'Not Cured' subjects, C2hr plasma levels after first dose at Day0 were significantly low (INH: 0.86 vs 2.94 μg/ml p≤0.002, RIF: 0.56 vs 2.55 μg/ml p≤0.003, PZA: 1.85 vs 26.58 μg/ml p≤0.000 and EMB: 0.72 vs 1.53 μg/ml p≤0.010). In contrast, STM levels were higher (31.84 vs 18.08 μg/ml p ≤0.007). Based on ROC analysis of the data, therapeutic indicator values for successful treatment outcome were C2hr plasma levels of 10.6 μg/ml for PZA, 1.14 &mug/ml for RIF, 1.86 μg/ml for INH and 1.24 μg/ml for EMB. Therapeutic failure in PTB patients on retreatment regimen is associated with lower plasma drug levels. Therapeutic drug monitoring would prove useful to maintain drug levels above the minimum cut-off levels for obtaining favorable clinical outcome.

Higher plasma drug levels in elderly people living with HIV treated with darunavir

Background The proportion of elderly people living with HIV-1 (PLHIV) is rising. In older patients, comorbidities and concomitant medications are more frequent, increasing the risk of potential drug-drug interactions (PDDIs). Data on the pharmacokinetics of ART in individuals aged ≥ 65 years of age are scarce. We compared plasma drug levels of ART, PDDIs, and side-effects in PLHIV aged ≥ 65 years of age, with controls ≤ 49 years of age. Methods Patients ≥ 65 years of age and controls ≤ 49 years of age, all of whom were on stable treatment with atazanavir (ATV), darunavir (DRV), or efavirenz (EFV) were included cross-sectionally. Plasma drug levels of ART were analyzed, comorbidities, concomitant medication, adherence, and side-effects recorded, and PDDIs analyzed using drug interactions databases. Results Between 2013 and 2015, we included 100 individuals ≥ 65 years of age (study group) and 99 controls (≤ 49 years of age). Steady-state DRV concentrations were significantly higher in the study group than in the control group (p = 0.047). In the ATV group there was a trend towards a significant difference (p = 0.056). No significant differences were found in the EFV arm. The DRV arm had a higher frequency of reported side-effects than the ATV and EFV arms in the study group (36.7% vs. 0% and 23.8% respectively (p = 0.014), with significant differences between DRV vs. ATV, and EFV vs. ATV). Conclusions Higher steady-state plasma levels of DRV and ATV (but not EFV) were found in PLHIV aged ≥ 65 years of age, compared to controls ≤ 49 years of age.

Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in persons with pancreatobiliary cancer or other mesothelin expressing solid tumors.

TPS452 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting with a modified Pseudomonas exotoxin A payload. Formation of anti-drug antibodies (ADAs) is thought to contribute significantly to limited clinical efficacy of LMB-100 seen in prior clinical trials. Most patients develop clinically meaningful ADAs after 1-2 cycles of LMB-100, resulting in rapid neutralization of LMB-100 during subsequent cycles and undetectable plasma drug levels. Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the treatment of rheumatoid arthritis and ulcerative colitis. Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs against recombinant immunotoxin (Onda et al. Journal of Immunology 2014), and that co-administration of tofacitinib with LMB-100 increases immunotoxin serum half- life in mice and anti-tumor efficacy (Simon et al. JCI Insight 2019). We hypothesize that co-administration of tofacitinib with LMB-100 will prevent or delay the formation of high titer ADAs to LMB-100, such that 2 effective cycles of immunotoxin can be administered to patients. Methods: This phase I clinical trial consists of a dose escalation phase using 3+3 design to determine the maximum tolerated dose (MTD) of LMB-100 that can be administered with tofacitinib in participants (n = 18 max) with mesothelin-expressing solid tumors, followed by a dose expansion phase at the MTD for participants (n = 15) with pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma. The primary objective of the expansion phase is to determine whether co-administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs for cycle 2 of treatment as measured by LMB-100 plasma drug levels. A positive outcome will be reached if percent of participants achieving threshold LMB-100 drug levels during cycle 2 increases from 50% to 80% (83.6% probability if >10 of 15 evaluable participants meet this milestone). Plasma drug levels during cycle 3 will also be analyzed as a secondary endpoint. Key inclusion criteria include adults with histologically confirmed previously treated solid tumor malignancies. Participants will receive tofacitinib 10 mg twice daily on days 1-10 and LMB-100 at 65, 100, or 140 mcg/kg on days 4, 6 and 8 of a 21-day cycle. The dose escalation phase has been completed and enrollment onto dose expansion phase is ongoing. Clinical trial information: NCT04034238.

Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.