RYGB and Drug Disposition: How to Do Better? Analysis of Pharmacokinetic Studies and Recommendations for Clinical Practice

International audienc

Morphine and metabolites plasma levels after administration of sustained release morphine in Roux-en-Y gastric bypass subjects versus matched control subjects

International audienceBackground: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population.Objective: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls.Settings: University hospital, Lariboisière Hospital, Paris.Methods: Thirty milligrams of morphine as a sustained-release formulation was orally administered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their nonsurgical controls matched for sex, body mass index (±2 points), and age (±5 yr). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period were determined by a validated method using liquid chromatography mass spectrometry in tandem. Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit.Results: Morphine oral area under the curve (for time 0-12 hr; 115.8 ± 108.0 nmol.hr/L and 86.9 ± 38.8 nmol.hr/L for RYGB group and control group, respectively, P = .71), morphine at maximal concentration, metabolites oral area under the curve (for time 0-12 hr), and other PK parameters were similar between groups. After drug administration, mean drowsiness was superior in RYGB group. Mean respiratory rate and oxygen saturation were similar in both groups.Conclusion: No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients

Novel mutations in antiviral multiresistant HSV‐2 genital lesion: A case report

HSV‐2 antiviral resistance mainly occurs in immunocompromised patients and especially in HIV‐positive individuals receiving long‐term antiviral treatment. Those situations can be challenging as few alternatives are available for HSV infection management. To describe clinical and virological significance of two novel potential HSV‐2 resistance mutations after treating an obese patient with a pseudotumoral genital HSV‐related lesion. Consecutive different antiviral treatments were used: valacyclovir (VACV) then foscarnet (FOS) then topical cidofovir (CDV) and finally imiquimod. Under VACV, genotypic resistance testing revealed a novel mutation within viral thymidine kinase (TK, gene UL23) not previously reported but probably accounting for antiviral resistance: W89G, similar to W88R mutation reported in HSV‐1 TK, known to be associated with ACV resistance for HSV‐1. Under FOS, while initial mutations were still present, a second genotypic resistance testing performed on persisting lesions showed a novel mutation within viral DNA polymerase (DNA pol, gene UL30): C625R. All three antivirals used in this case are small molecules and pharmacokinetics of VACV, FOS, and CDV have not been evaluated in animals and there are very few studies in human. As small molecules are poorly bound to proteins and distribution volume is increased in obese patients, there is risk of underdosage. This mechanism is suspected to be involved in emergence of resistance mutation and further data is needed to adapt, closely to patient profile, antiviral dosage. This report describes a chronic HSV‐2 genital lesion, with resistance to current antivirals and novel mutations within viral TK and DNA pol which may confer antiviral resistance

Combined Nivolumab and Ipilimumab in Octogenarian and Nonagenarian Melanoma Patients

International audienceData regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). Here, we ask what are the current prescribing patterns of NIVO + IPI in the very elderly population and analyze the tolerance profile. This French multicenter retrospective study was conducted on 60 melanoma patients aged 80 years and older treated with NIVO + IPI between January 2011 and June 2022. The mean age at first NIVO + IPI administration was 83.7 years (range: 79.3–93.3 years). Fifty-five patients (92%) were in good general condition and lived at home. Two dosing regimens were used: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (NIVO1 + IPI3) in 27 patients (45%) and NIVO 3 mg/kg + IPI 1 mg/kg Q3W (NIVO3 + IPI1) in 33 patients (55%). NIVO + IPI was a first-line treatment in 39 patients (65%). The global prevalence of immune-related adverse events was 63% (38/60), with 27% (16/60) being of grade 3 or higher. Grade ≥ 3 adverse events were less frequent in patients treated with NIVO3 + IPI1 compared with those treated with NIVO1 + IPI3 (12% versus 44%, p = 0.04). In conclusion, the prescribing patterns of NIVO + IPI in very elderly patients are heterogeneous in terms of the dosing regimen and line of treatment. The safety profile of NIVO + IPI is reassuring; whether or not the low-dose regimen NIVO3 + IPI1 should be preferred over NIVO1 + IPI3 in patients aged 80 years or older remains an open question