Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.

RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted. STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan. SETTING & PARTICIPANTS: Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure. INTERVENTION: Tolvaptan administered twice daily in split-dose regimens. OUTCOMES: Frequency of liver enzyme level increases detected by regular laboratory monitoring. RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan. LIMITATIONS: Retrospective analysis. CONCLUSIONS: The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label. FUNDING: Otsuka Pharmaceutical Development & Commercialization, Inc. TRIAL REGISTRATION: Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).

Trametinib-Resistant Melanoma Cells Displaying MITFhigh/NGFRlow/IL-8low Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge.

Despite significant advances in targeted therapies against the hyperactivated BRAFV600/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib, an agent broadly used in combination therapies. Molecular and cellular changes were assessed during alternating periods of trametinib withdrawal and rechallenge in trametinib-resistant cell lines displaying either a differentiation phenotype (MITFhigh/NGFRlow) or neural crest stem-like dedifferentiation phenotype (NGFRhigh/MITFlow). Neither drug withdrawal nor drug rechallenge induced cell death, and instead of loss of fitness, trametinib-resistant melanoma cells adapted to altered conditions by phenotype switching. In resistant cells displaying a differentiation phenotype, trametinib withdrawal markedly decreased MITF level and activity, which was associated with reduced cell proliferation capacity, and induced stemness assessed as NGFR-positive cells and senescence features, including IL-8 expression and secretion. All these changes could be reversed by trametinib re-exposure, which emphasizes melanoma cell plasticity. Trametinib-resistant cells displaying a dedifferentiation phenotype were less responsive presumably due to the already low level of MITF, a master regulator of the melanoma phenotype. Considering new directions of the development of anti-melanoma treatment, our study suggests that the phenotype of melanomas resistant to targeted therapy might be a crucial determinant of the selection of second-line therapy for melanoma patients.

Cost of managing severe cutaneous adverse drug reactions to first-line tuberculosis therapy in South Africa.

OBJECTIVE: To compare the cost of managing treatment-limiting cutaneous adverse drug reactions (CADRs) to first-line anti-tuberculosis drugs to an alternative strategy of immediate treatment initiation using second-line drugs in a South African setting. METHODS: Clinical and cost data were retrospectively collected from patients presenting with a first-line anti-tuberculosis therapy-associated CADR. Costs (2016 US$) were estimated using an ingredient's approach from a healthcare provider perspective. The per-patient and total cost of drug rechallenge, the current management strategy for severe CADR, was calculated. Alternative strategies involving second-line treatment were derived from literature and expert clinical advice. RESULTS: Drug rechallenge costs US $5831 (95% CI: 5134-6527) per patient. Hospitalisation accounted for 62% of this cost. Alternative CADR management strategies using regimens containing rifabutin, bedaquiline and/or delamanid cost 44%-55% less than drug rechallenge (US $2651-US $3276/patient). In univariate sensitivity analyses, drug rechallenge and alternative strategies were most sensitive to hospitalisation and tuberculosis drug costs, respectively. CONCLUSION: Cutaneous adverse drug reactions to anti-tuberculosis treatment represent a significant economic burden. An alternate strategy of outpatient-initiated second-line therapy is economically feasible but requires clinical validation to assess effectiveness.

OBJECTIF: Comparer le coût de la prise ne charge des effets indésirables cutanés (EIC) limitant le traitement aux antituberculeux de première ligne à celui d'une stratégie alternative d'initiation immédiate du traitement par des médicaments de deuxième ligne dans un contexte sud-africain. MÉTHODES: Les données cliniques et les coûts ont été collectés rétrospectivement chez des patients présentant un EIC associé au traitement antituberculeux de première ligne. Les coûts (USD, 2016) ont été estimés en utilisant une approche d'ingrédient du point de vue d'un prestataire de soins de santé. Le coût par patient et le coût total du nouveau traitement, de la stratégie actuelle de prise en charge des cas d'EIC sévère, ont été calculés. Des stratégies alternatives impliquant un traitement de deuxième ligne ont été dérivées de la littérature et de conseils cliniques d'experts. RÉSULTATS: Le coût du nouveau traitement était de 5.831 USD (IC95%: 5.134 - 6.527) par patient. L'hospitalisation représentait 62% de ce coût. Les stratégies alternatives de prise en charge des EIC utilisant des schémas thérapeutiques contenant de la rifabutine, de la bédaquiline et/ou du delamanide coûtent de 44 % à 55 % moins cher que le nouveau traitement (2.651 USD - 3.276 USD/patient). Dans les analyses de sensibilité univariées, les stratégies de re-traitement et les stratégies alternatives étaient plus sensibles aux coûts d'hospitalisation et de médicaments antituberculeux, respectivement. CONCLUSION: Les EIC des antituberculeux représentent une charge économique importante. Une stratégie alternative de traitement de deuxième ligne mise en place chez des patients ambulatoires est économiquement réalisable mais nécessite une validation clinique pour évaluer l'efficacité.

Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal.

BACKGROUND: Although BRAFV600/MEK inhibitors improved the treatment of melanoma patients, resistance is acquired almost inevitably. METHODS: Trametinib withdrawal/rechallenge and MCL-1 inhibition in trametinib-resistance models displaying distinct p-ERK1/2 levels were investigated. RESULTS: Trametinib withdrawal/rechallenge caused reversible changes in ERK1/2 activity impacting the balance between pro-survival and pro-apoptotic proteins. Reversible alterations were found in MCL-1 levels and MCL-1 inhibitors, BIM and NOXA. Taking advantage of melanoma cell dependency on MCL-1 for survival, we used S63845. While it was designed to inhibit MCL-1 activity, we showed that it also significantly reduced NOXA levels. S63845-induced apoptosis was detected as the enhancement of Annexin V-positivity, caspase-3/7 activation and histone H2AX phosphorylation. Percentages of Annexin V-positive cells were increased most efficiently in trametinib-resistant melanoma cells displaying the p-ERK1/2low/MCL-1low/BIMhigh/NOXAlow phenotype with EC50 values at concentrations as low as 0.1 µM. Higher ERK1/2 activity associated with increased MCL-1 level and reduced BIM level limited pro-apoptotic activity of S63845 further influenced by a NOXA level. CONCLUSIONS: Our study supports the notion that the efficiency of an agent designed to target a single protein can largely depend on the phenotype of cancer cells. Thus, it is important to define appropriate phenotype determinants to stratify the patients for the novel therapy.