BACKGROUND: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine. METHODS: This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade ≥3. Non-inferiority was determined by checking whether the upper bound of the twosided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin. RESULTS: In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade ≥3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference −2.7% (90% CI: −6.2 to 0.1). CONCLUSIONS: As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine. CLINICAL TRIAL REGISTRATION: www.trialregister.nl; NL8173.

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Owing to significant dose-related toxicity, the adult stavudine dose was reduced in 2007. The paediatric dose, however, has not been reduced. Although the intended paediatric dose is 1 mg/kg twice daily (b.i.d.), the current weight-band dosing approach results in a mean actual dose of 1.23 ± 0.47 mg/kg. Both efficacy and mitochondrial toxicity depend on the concentration of the intracellular metabolite stavudine triphosphate (d4T-TP). We simulated the effect of reducing the paediatric dose to 0.5 mg/kg. A physiologically-based pharmacokinetic model consisting of 13 tissue compartments plus a full ADAM model was used to describe the elimination of stavudine. The volume of distribution at steady-state and apparent oral clearance were simulated and the resulting AUC profile was compared with literature data in adult and paediatric populations. A biochemical reaction model was utilised to simulate intracellular d4T-TP levels for both the standard and proposed reduced paediatric doses. Simulated and observed exposure after oral dosing showed adequate agreement. Mean steady-state d4T-TP for 1.23 mg/kg b.i.d. was 27.9 (90% CI 27.0–28.9) fmol/106 cells, 25% higher than that achieved by the 40 mg adult dose. The 0.5 mg/kg dose resulted in d4T-TP of 13.2 (12.7–13.7) fmol/106 cells, slightly higher than the adult dose of 20 mg b.i.d. [11.5 (11.2–11.9) fmol/106 cells], which has excellent antiviral efficacy and substantially less toxicity. Current paediatric dosing may result in even higher d4T-TP than the original 40 mg adult dose. Halving the paediatric dose would significantly reduce the risk of mitochondrial toxicity without compromising antiviral efficacy.

With great interest, we read the research article of Lala et al. [1]. The authors present a robust population pharmacokinetic (PPK) model of pembrolizumab with data from 2993 patients and a thorough data interpretation. This research gives a better insight into the exposureeeresponse relationship for pembrolizumab, and they concluded that a dose of 2 mg/kg or a fixed dose of 200 mg every 3 weeks (Q3W) can be extended to a dose of 400 mg Q6W based on pharmacokinetic modelling. Although this study provides clear dosing

was overall survival (OS). Survival was estimated by KaplaneMeier method, and comparisons performed with log-rank test.Results: A total of 167 pts were included: median age was 55 years (18À81), 55.7% were females, 91% had an ECOG-PS !2, 75.4% had gastrointestinal primary tumors, and 70.1% had no previous systemic treatment. Median time from cancer diagnosis to MBO was 16 weeks (0-972.4), and median length of hospitalization after CTX was 2 weeks (0.1-13.6). Overall, a total of 159 deaths were observed, with a median OS of 4.4 weeks (95% confidence interval [CI], 3.4-5.5) after CXT administration, and 5.6 weeks (95% CI, 4.6-6.5) after MBO diagnosis. Treatment line, ECOG-PS and primary tumor did not impact OS. Intestinal function recovery was observed in 86 pts (51.5%) after CTX, out of whom 22 (25.5%) had a re-obstruction. Pts who recovered intestinal function had a longer OS when compared to those who did not (10 weeks vs. 2.1 weeks; p<0.001). Hospital discharge was possible in 51.5% of the pts, and it was significantly correlated with intestinal function recovery (p<0.001). Grade !3 toxicities occurred in 26.9% of the pts after CTX.Conclusions: MBO was associated with a poor prognosis in this mostly treatment naive population. The administration of CTX yielded a significant risk of toxicities, whereas it may provide a modest benefit of questionable clinical relevance in this scenario.Legal entity responsible for the study: The authors.