Dosing Interval Research Articles

Medication refills do not guarantee medication intake: translation and validation of the adherence to refills and medications scale in traditional Chinese among individuals with type 2 diabetes in Taiwan

ABSTRACT Objective This study aimed to translate and validate the Adherence to Refills and Medications Scale into Traditional Chinese (ChARMS-T) and to investigate common barriers to medication adherence among patients with type 2 diabetes (T2D) in Taiwan. Methods The ChARMS-T was developed through translation and application phases. During the translation phase, the scale underwent forward translation, backward translation, and cognitive debriefing. In the application phase, the finalized ChARMS-T was administered to patients with T2D at five Taiwan community pharmacies over nine months starting in September 2023. Psychometric properties were assessed using criterion validity, construct validity through confirmatory factor analysis, and reliability through McDonald’s omega. Results A total of 343 participants completed surveys. Factor analysis of the 12-item ChARMS-T revealed two dimensions: medication-taking (8 items) and medication refill (4 items). The instrument demonstrated acceptable internal consistency, with McDonald’s omega scores of 0.841 for medication-taking and 0.647 for medication refill. The medication refill subscale showed strong agreement with the objective refill measure, proportion of days covered, with a coefficient of 0.84, suggesting that these measures evaluate similar constructs. Evidence of known-groups validity was demonstrated by a significant difference between ChARMS-T scores and glycemic control (p = 0.047). Patients with good glycemic control had a significantly higher adherence rate to both refills and medication-taking compared to those with poor glycemic control. The most frequently reported barriers to medication-taking were carelessness (55.7%), forgetfulness (54.8%), and frequent dosing intervals (43.1%). For medication refills, 9.6% of the participants identified a lack of planning as the main reason for not refilling their diabetes medications on time, followed by forgetfulness (7.6%). Conclusions The ChARMS-T identified a broader range of non-adherence reasons and demonstrated good psychometric properties. It can be integrated into practice settings for screening and follow-up to enhance medication adherence through effective communication between healthcare professionals and patients, ultimately improving long-term patient health outcomes.

Optimization of antiviral dosing in Herpesviridae encephalitis: a promising approach to improve outcome?

Despite established antiviral therapy for herpes simplex (HSV), varicella zoster (VZV) and cytomegalovirus (CMV) encephalitis, outcome remains poor. To assess pharmacokinetic (PK) and -dynamic (PD) data of antiviral drugs in the central nervous system (CNS) to optimize treatment of Herpesviridae encephalitis. PUBMED search 1950 to September 2024, terms 1. "encephalitis" and ("HSV" or "VZV" or "CMV") or 2. cerebrospinal and ["(val)acyclovir" or "(val)ganciclovir" or "foscarnet" or "cidofovir"]. Antivirals against herpes viruses apparently act in a time-dependent manner. To suppress viral replication, drug concentration in the extracellular space at the site of the infection should be kept above the concentrations active in cell cultures for 24h per day. Most data reflect delayed drug entry into lumbar cerebrospinal fluid (CSF). Ratios of the areas of the concentration/time curves (AUC) in CSF and serum (AUCCSF/AUCS) of acyclovir, ganciclovir and foscarnet are 0.15-0.3 in the absence of meningeal inflammation and increase in severe meningoencephalitis. Elimination half-lives (t1/2β) are longer in CSF than in plasma. CSF concentrations are rough approximations of drug concentrations in the cerebral extracellular fluid (ECF). Lumbar CSF concentrations usually are higher than ventricular or cisternal CSF concentrations tending to overestimate cerebral ECF concentrations. Provided the availability of adequate measurements in individual CNS compartments - antiviral concentrations and efficacy may be predicted by future PK/PD modeling. Probenecid holds potential to reduce efflux of antiviral drugs from the CNS. The long t1/2β of antiviral drugs in CSF suggest relatively uniform steady state CSF levels at dosing intervals ≤12h and accumulation after repeated dosing. Probenecid is of unproven utility. To rapidly attain effective concentrations in the infected tissue, physiologically based pharmacokinetic (PBPK) and PK/PD modeling may be helpful. Until reliable PK/PD data are available, doubling the first dose should be considered.

Abstract IA008: Leveraging conformational dynamics for improved selectivity

Abstract Maximizing the clinical activity and combinability of oncogene inhibitors requires the development of molecules that can achieve necessary levels of target inhibition at a tolerated and feasible human dose. This is enabled by improving selectivity against off-targets and/or for the mutant form of the target over wild-type. While conventional structural insights can inform the design of selective drug candidates, there are often cases where clear selectivity hypotheses are not readily identifiable. Here, we present two examples illustrating how conformational dynamics can be leveraged to obtain improved selectivity for validated oncogene targets. The first example focuses on the selective inhibition of FGFR2, a well-established target in various cancers harboring FGFR2 fusions or rearrangements. Although clinical efficacy of pan-FGFR inhibitors has been demonstrated, their benefit is limited by FGFR1- and FGFR4- mediated toxicities. We leveraged differences in conformational dynamics between FGFR2 and other FGFRs observed through molecular dynamics simulations to enable the development of Lirafugratinib, the first FGFR2 selective inhibitor. Lirafugratinib inhibits FGFR2 with a high degree of selectivity in pre-clinical models. In cancer patients, Lirafugratinib achieves >95% FGFR2 occupancy at a dose of 70mg once daily, with minimal evidence of inhibition of other FGFR isoforms. This improved selectivity translates to higher objective response rates compared to pan-FGFR inhibitors across multiple tumor types harboring FGFR2 fusions or rearrangements. The second example illustrates mutant-selective targeting of PI3Kα, the most frequently mutated kinase in cancer. While non-mutant selective inhibitors have shown clinical efficacy, their benefit is limited by hyperglycemia caused by inhibition of wild-type PI3Kα. Conformational differences between mutant and wild-type PI3Kα were identified using structural insights combined with molecular dynamics simulations, leading to the discovery of RLY-2608- the first mutant-selective inhibitor of PI3Kα. RLY-2608 binds to a novel allosteric pocket and demonstrates mutant selective inhibition in pre-clinical models. RLY-2608 has a favorable pharmacokinetic profile in cancer patients, with dose-dependent increases in exposure and low peak to trough fluctuations, resulting in high levels of target coverage throughout the dosing interval. When combined with fulvestrant, this translates into a higher objective response rate and lower rate of hyperglycemia in patients with hormone-receptor positive, PI3Kα-mutant breast cancer compared to non-mutant selective PI3Kα inhibitors. These examples demonstrate the power of leveraging conformational dynamics to obtain selective target inhibition, ultimately translating into improved patient outcomes. Citation Format: James Watters. Leveraging conformational dynamics for improved selectivity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA008.

Optimal Blood Sampling Time for Area under the Concentration-Time Curve Estimation of Vancomycin by Assessing the Accuracy of Four Bayesian Software.

Effective blood sampling times, beyond trough and peak levels, have not been determined for estimating vancomycin's area under the concentration-time curve (AUC) using the Bayesian software. The aim of this study was to evaluate the accuracy of AUC estimation at different blood sampling times during the same dosing interval at steady state utilizing data from a prior phase I trial of vancomycin. Six healthy adult participants were sampled following intravenous administration of 1 g vancomycin for 1.5 h every 12 h. The AUC was estimated using four software packages and four population pharmacokinetic models. Accuracy was assessed using bias (difference between the estimated and reference AUC) and imprecision (absolute percentage difference between the estimated and reference AUC). The accuracy varied with the sampling time. The optimal two-point sampling times were determined to be 2.5 and 5.5 h post-injection using software packages for EasyTDM, Practical AUC-guided therapeutic drug monitoring (TDM), and Anti-MRSA Agents TDM Analysis Software (incorporating Rodvold, Yamamoto, and Yasuhara models). In these estimations, the mean bias (range, -1.7 to 9.5 µg·h/mL) was unbiased and the mean imprecision (range, -3.0% to 5.0%) was precise. The optimal one-point sampling time was 5.5 h post-injection for Anti-MRSA Agents TDM Analysis Software, which incorporated the Yamamoto and Yasuhara models. In conclusion, optimal blood sampling times may vary depending on the software and model used. Our findings suggest that identifying specific sampling times could improve the efficacy of TDM in clinical practice.

P14 A multicentre, randomized, double-blind, placebo-controlled Phase II study to evaluate the efficacy and safety of individual dose regimens of HB0017 in patients with moderate-to-severe plaque psoriasis

Abstract HB0017 is a recombinant humanized IgG1 monoclonal antibody that targets IL-17A. To investigate HB0017 optimal dosage and possible dosing interval during maintenance therapy to inform Phase III studies. A total of 81 patients with moderate-to-severe plaque psoriasis received HB0017 300 mg (n = 41) or placebo (n = 40) at Weeks 0, 1, 2, 4, and 8. From Week 12 to Week 28, patients in the HB0017 group were given HB0017 300 mg once every 8 weeks. And patients in the placebo group were given HB0017 300 mg at Week 12, 13, 14 and 16, and then every 4 weeks until Week 28. Efficacy, safety, pharmacokinetics, and immunogenicity were assessed in Week 36. After 12 weeks of treatment, HB0017 300 mg resulted in significantly higher PASI 90 and sPGA0/1 response rates vs. placebo (P < 0.001). At Week 12, in the HB0017 group, 69.4% of patients achieved PASI 90, increasing to 97.6% at Week 24, then maintained throughout the follow-up period. And 78.2% of patients achieved sPGA0/1, increased to comparable peak levels at Week 28(97.6%), then maintained to Week 36(97.5%). In the placebo group, 1.0% of patients achieved PASI 90 at Week 12, increased to 94.3% at Week 28, then maintained throughout the follow-up period. 1.1% of patients achieved sPGA0/1, increased to 91.2% at Week 24, then maintained to Week 36(91.4%). The overall safety profile of HB0017 was similar to those of similar drugs, and no new safety signals were identified. These data provide evidence to support the evaluation of HB0017 300 mg maintenance dosing both every 8 and every 4 weeks in Phase III clinical trials.

Determination of pharmacokinetic-pharmacodynamic cutoff values of oxytetracycline in calves and adult cattle using population pharmacokinetic modeling.

A harmonized clinical breakpoint for interpreting antimicrobial susceptibility testing of oxytetracycline in cattle is currently lacking in Europe. This study aimed to establish a pharmacokinetic/pharmacodynamic (PK/PD) cutoff to propose clinical breakpoints, facilitating reliable interpretation of antimicrobial susceptibility results in cattle. A meta-analysis of oxytetracycline pharmacokinetic data from 69 cattle was conducted, including 1,730 plasma concentration samples from animals administered 20 mg/kg intramuscularly and/or 20 or 40 mg/kg intravenously. A three-compartment model with two absorption phases was selected, incorporating age as a covariate for clearances and distribution volumes. The PK/PD cutoff was defined as the maximum MIC for which the fAUC/MIC index achieves the pharmacodynamic target in 90% of cattle given the standard dosing regimen. The pharmacodynamic index (PDI) target selected was established to 24 h, i.e., the average free plasma concentration of oxytetracycline over the 24-h dosing interval, under steady-state conditions, is equal to the selected MIC. Simulations indicated a PK/PD cutoff of 2 mg/L in adult cattle and 1 mg/L in calves for intramuscularly administered long-acting products at 20 mg/kg with a 48-hour efficacy duration. The difference is attributed to higher clearance rates in calves. The established PK/PD cutoffs, when used alongside the wild-type bacterial epidemiological cutoff, can aid in setting clinical breakpoints for oxytetracycline, supporting effective antimicrobial therapy in cattle and accounting for age-related pharmacokinetic differences.

Comparison of On-Label Treatment Persistence in Real-World Patients with Psoriatic Arthritis Receiving Guselkumab Versus Subcutaneous Interleukin-17A Inhibitors.

Psoriatic arthritis (PsA) is a chronic, multidomain, inflammatory disease requiring long-term treatment. Guselkumab, a fully human interleukin [IL]-23p19-subunit inhibitor, and the IL-17A inhibitors (IL-17Ai) ixekizumab and secukinumab are approved by the US Food and Drug Administration (FDA) for adults with active PsA. Real-world data evaluating on-label treatment persistence is an important consideration for patients. This retrospective claim-based analysis (IQVIA PharMetrics® Plus) included adults with PsA receiving guselkumab or their first subcutaneous (SC) IL-17Ai (ixekizumab/secukinumab) per FDA label ("on-label") between July 14, 2020, and June 30, 2022. Baseline demographicanddisease characteristics were collected in the 12 months preceding the index date (date of first guselkumab or SC IL-17Ai claim); follow-up extended through the earlier of theend of continuous insurance eligibility or end of data availability. Baseline characteristics were balanced between the cohorts by propensity score weighting (standardized mortality ratio [SMR]). Discontinuation was defined as a gap 2 × the FDA-approved maintenance dosing interval (guselkumab:112 days; SC IL-17Ai: 56 days); on-label persistence in the weighted cohorts was assessed using Kaplan-Meier curves and compared with a Cox proportional hazards model. Weighted demographic and disease characteristics were well balanced between the cohorts (guselkumab: N = 910, mean age = 50.4 years, 60.4% female; SC IL-17Ai: N = 2740, mean age = 50.2, 59.4% female). At 12 months, the guselkumab cohort was 1.85 × more likely to remain persistent with on-label therapy vs the SC IL-17Ai cohort (p < 0.001); median time to discontinuation was not reached for guselkumab and was12.3 months for SC IL-17Ai. At 3, 6, 9, and 12 months, persistence rates in the weighted cohorts were higher with guselkumab than with SC IL-17Ai (p < 0.001). In this real-world claims data analysis in adults with PsA, on-label persistence rates were statistically significantly higher with guselkumab, as early as 3 months, with ~ 2 × greater likelihood of persistence at 12 months relative to SC IL-17Ai.

Population pharmacokinetic analysis of quizartinib in patients with newly diagnosed FLT3-internal-tandem-duplication-positive acute myeloid leukemia.

The population pharmacokinetics (PK) of quizartinib and its pharmacologically active metabolite AC886 have been previously described in healthy volunteers (HV) and relapsed/refractory (R/R) FLT3-internal-tandem-duplication-positive (FLT3-IDT-positive) acute myeloid leukemia (AML) patients receiving quizartinib monotherapy. In this analysis, we characterized the population PK of quizartinib and AC886 in newly diagnosed FLT3-ITD-positive AML patients receiving standard induction and consolidation chemotherapy as background treatment, using data from the Phase 3 QuANTUM-First trial and 12 earlier studies. Quizartinib PK were best described by a three-compartment model with sequential zero- and first-order absorption and first-order elimination. A two-compartment model with first-order metabolite formation and first-order elimination best fitted AC886 data. The PK of both moieties showed large interindividual variability (approximately 70% coefficient of variation for systemic clearances). The use of strong cytochrome P450 3A (CYP3A) inhibitors had the largest impact on exposure, increasing the steady-state area under the curve during the dosing interval (AUCss) by 1.8-fold. This is consistent with observations in HV and R/R AML patients and confirms the need for dose adjustments during coadministration. A novel finding in newly diagnosed AML patients was the phase-dependent change in steady-state quizartinib exposure: dose-normalized AUCss values were 0.6-fold during induction, similar during consolidation, and 1.4-fold during continuation compared to R/R AML patients receiving quizartinib monotherapy. The present analysis highlighted the comparison of quizartinib and AC886 PK between newly diagnosed AML patients and previously studied populations, informed dose modifications needed with strong CYP3A inhibitors, and supported the use of derived individual exposure metrics in separate exposure-response analyses.

Involuntary medication treatment of schizophrenia in the inpatient setting

Abstract Two Supreme Court cases in the United States describe the use of involuntary medication in individuals with mental illnesses. In addition to these legal requirements, clinicians must also incorporate ethics into treating these individuals, including the principles of autonomy and beneficence. Current guidelines do not provide specific recommendations for choosing an antipsychotic for a patient with schizophrenia who is being treated involuntarily. However, it is recommended that clinicians use general guidelines for the treatment of schizophrenia as a basis for narrowing down appropriate therapy, which may involve the use of long-acting injectable antipsychotics. Clinical considerations that should be accounted for include past medication trials, potential adverse effects, whether tolerability has been demonstrated, route of administration, dosing interval, requirement for oral overlap, comorbid conditions, patient preference, and access to the medication.

Luminescência opticamente estimulada em pastilhas de quartzo utilizando iluminação azul e verde

In this study, pellets fabricated from powdered rose quartz are investigated for their potential as ionizing radiation detectors, taking advantage of the abundant availability of quartz in the Earth's crust. For this purpose, optically stimulated luminescence (OSL) technique, using blue and green light stimulation, was used. The pellets were irradiated with a 90Sr/90Y beta source to doses from 80 to 550 mGy (dose rate = 0.08Gy/s). Analysis of the OSL decay curves showed a good fit with 3 exponential components (fast, medium, and slow). A linear dose-response relationship was observed within this interval of dose for both light stimulations. The repeatability of the OSL signal was found to be 3% for blue light and 2% for green light. Additionally, the fading experiment indicated that, after 1 hour, 41% and 35% of the OSL signal remains for blue and green stimulation, respectively. The results obtained highlight the promising usefulness of rose quartz-based pellets as effective detectors of ionizing radiation.

One Concentration Does Not Fit All: It is Time to Personalize the Therapeutic Range of Infliximab in Crohn Disease.

Therapeutic drug monitoring of infliximab is commonly performed based on trough concentration. However, doses and dosing intervals may be adapted to patient outcomes, and this trough concentration target may correspond to a large range of exposures in terms of the area under the concentration-time curve (AUC). The objectives of this study were to assess the real-life exposure to intravenous infliximab in patients with Crohn disease in remission at year 1 and to assess the evolution of exposure in patients who switched to subcutaneous infliximab. The authors conducted a retrospective observational pharmacokinetic study in patients with Crohn disease who had available infliximab concentrations during intravenous and subcutaneous infliximab maintenance therapy as per the standard of care. Infliximab exposure parameters (AUCs and trough concentrations, C0) were compared for different dosing regimens of intravenous infliximab before (intravenous) and after (subcutaneous) the switch. A total of 113 patients had 383 intravenous infliximab concentrations. Dosing intervals ranged from 4 to 12 weeks. The median/range/CV% C0, AUC0-t, and AUC0-8weeks were 5.3 mcg/mL [<LLoQ-49.6]/71.6%, 37,792 mcg.h/mL [4971-116,366]/33.1%, and 41,582 mcg.h/mL [7953-232,048]/43.9%, respectively. Forty-one patients had available paired C0 after both intravenous and subcutaneous administration. A poor correlation was found between preswitch intravenous infliximab C0 and postswitch subcutaneous infliximab C0. In this study, the authors suggested that in patients treated with IV IFX, different targets of C0 should be proposed according to treatment schemes and that AUC0-t might be a relevant determinant of clinical remission. Moreover, exposure did not remain stable throughout the switch from IV to SC IFX in any patient. These variations may depend on the intravenous dosing interval before switching.

Assessing Antiparasitic Compounds Persistence in Cattle Hair by DART-MS.

This study introduces an alternative strategy for evaluating antiparasitic persistence compounds in cattle hair by Direct Analysis in Real Time Mass Spectrometry (DART-MS). The developed DART-MS method aimed to determine fenthion, chlorpyrifos, and cypermethrin in cattle hair samples. DART-MS analyses were performed in positive ion mode, and parameters related to the DART source were evaluated. The analytical performance demonstrated the efficiency of the optimized DART-MS method for fenthion, chlorpyrifos, and cypermethrin quantification in the evaluated samples, meeting criteria for precision, accuracy and limits of detection. Overall, the DART-MS method provided a fast and efficient analysis for determination of antiparasitic agents in cattle hair, which contributes to the evaluation of drug administration protocols and dosage intervals, and aids the safety and advancement of the livestock sector.

Pharmacokinetics of Tarlatamab, a Delta-Like Ligand-3 (DLL3) Targeted Half-Life Extended Bispecific T-Cell Engager (BiTE®) Immunotherapy in Adult Patients with Previously Treated Small-Cell Lung Cancer: Results from DeLLphi-300, a Phase I Multiple-Dose-Escalation Study.

Tarlatamab binds to delta-like ligand 3 on cancer cells and cluster of differentiation-3 on T cells, leading to T-cell-mediated tumor lysis, and has demonstrated a promising safety and efficacy profile in patients with previously treated small-cell lung cancer (SCLC). Here, we present pharmacokinetic results from DeLLphi-300 (NCT03319940), an ongoing international, open-label, first-in-human study in previously treated adult patients with SCLC. Multiple escalating doses of tarlatamab were administered every 2 weeks (Q2W; 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mg) in a 28-day cycle. To reduce the risk of cytokine-release syndrome, starting at the 3 mg dose level, a step dose regimen was employed consisting of a 1 mg infusion on cycle 1 day 1 (C1D1), followed by the target dose on C1D8, C1D15, and Q2W thereafter. All doses were infused over 1 h. Other tarlatamab dosing regimens were also explored, either for patient convenience (every 3 weeks) or to mitigate cytokine-release syndrome (extended intravenous infusion over a period of 3 days). Intensive pharmacokinetic samples were collected during cycles 1 and 2, and additional samples for pharmacokinetic and immunogenicity measurement were collected at regular intervals in later cycles. Pharmacokinetic data were analyzed using noncompartmental analysis, and antidrug antibody (ADA) incidence, including any effect on tarlatamab pharmacokinetic parameters, was summarized. Pharmacokinetic data were available from 203 patients. The median age was 62 years (range 32-80), and 55.7% (n = 113) of patients were male, 78.3% (n = 159) were white, and 8.3% (n = 17) were of Japanese descent. Following intravenous infusion, serum tarlatamab concentrations declined with time in a biphasic manner. Serum exposures increased in an approximately dose-proportional manner across the evaluated target dose range with a mean (standard deviation) estimated terminal phase elimination half-life of 5.8 (1.6) days, and steady state achieved by approximately C2D15. Of the 183 evaluable patients, 12 (6.6%) developed treatment-emergent ADAs; the distribution of dose-normalized serum concentrations were similar between patients who were ADA positive and ADA negative. In addition, the distribution of exposures was comparable in Japanese and non-Japanese patients. In patients with previously treated SCLC, tarlatamab demonstrated dose-proportional pharmacokinetic and extended half-life characteristics that support a Q2W dosing interval. Neither Japanese race nor ADA had a clinically relevant impact on exposures.

The steady-state pharmacokinetics of fixed-dose combination dolutegravir+rilpivirine in hemodialysis

Objective: Fixed dose combination (FDC) dolutegravir (DTG) plus rilpivirine (RPV) is an approved antiretroviral treatment regimen for people with HIV. The steady-state pharmacokinetics (PK) of FDC DTG+RPV in hemodialysis (HD) has not been previously studied. Design: We performed a single-center, prospective evaluation of the steady-state PK of FDC DTG +RPV in 4 adults without HIV either requiring HD and in 4 matched participants with normal renal function. Methods: All participants received FDC DTG(50mg)+RPV(25mg) daily for 10-14 days with food before undergoing an intensive 24-hour PK evaluation (performed between dialysis days for those requiring HD). Plasma drug and metabolite concentrations were measured using a validated UHPLC/MS/MS. Descriptive PK parameters were calculated. Results: The HD and normal renal function participants (each group with 2 men and 2 women) were of similar ages (range, 50-60 years) and body mass index (range, 18.5-34.5 kg/m2). No participant experienced serious or grade 3-4 adverse events; there were no study discontinuations. The AUC0-τ mean (SD) ratios of HD to normal renal function for DTG and RPV were 1.1 (0.4) and 1.1 (0.9), respectively. The mean (SD) Cmin for DTG and RPV in the HD group were 1033 (252) ng/mL and 49 (18) ng/mL, respectively. Conclusions: HD did not lead to clinically appreciable differential exposures to DTG and RPV. Exposures throughout the dosing interval were greater than the reported protein-binding adjusted IC90 efficacy values for DTG (64 ng/mL) and RPV (12 ng/mL) in all participants. These data suggest no dosing modifications are needed for the FDC DTG+RPV regimen in HD.

Four-weekly dosing intervals with subcutaneous spesolimab appear to be required for optimal prevention of generalized pustular psoriasis flares: Data from the EFFISAYIL® 2 and EFFISAYIL® ON trials

Generalized pustular psoriasis (GPP) is a rare chronic skin disease characterized by recurrent, acute, and often life-threatening flares of widespread neutrophilic sterile pustules and systemic inflammation. Spesolimab, an anti-interleukin-36 receptor antibody, is approved in adults and adults and pediatric patients 12 years of age and older and weighing at least 40 kg, as a subcutaneous dosage for treatment of GPP when not experiencing a flare, and as an intravenous dosage for GPP flare treatment. In Effisayil 2, a randomized, placebo-controlled trial (NCT04399837), subcutaneous spesolimab was superior to placebo and well tolerated for flare prevention when administered as a 600-mg subcutaneous loading dose followed by 300 mg every 4 weeks (q4w) over 48 weeks. In Effisayil 2, 3/30 (10.0%) patients receiving subcutaneous spesolimab 300 mg q4w had flares, and there were no flares after Week 4 until the end of the study. We assessed the effect on flare recurrence of a longer (q12w) interval between subcutaneous spesolimab doses in Effisayil 2 and Effisayil ON (NCT03886246), an ongoing open-label extension trial. Flares were defined as a ≥2-point increase in GPP Physician Global Assessment total score with pustulation subscore of ≥2, or intravenous spesolimab or standard of care treatment due to GPP worsening. In Effisayil 2, 9/31 (29.0%) patients who received subcutaneous spesolimab 300 mg q12w had a flare; of those, 7/9 (77.8%) experienced a flare before their second subcutaneous dose (Week 12), and 5/7 (71.4%) flares occurred during Weeks 4–12, indicating the need for q4w dosing. In Effisayil ON, 36/108 (33.3%) patients who started q12w dosing were either escalated to a q4w regimen (n=24) or experienced a flare (n=12). These observations suggest that subcutaneous spesolimab 300 mg q4w is the optimal dosing regimen for prevention of GPP flares.

Greater preservation of SARS-CoV-2 neutralising antibody responses following the ChAdOx1-S (AZD1222) vaccine compared with mRNA vaccines in haematopoietic cell transplant recipients.

Whilst SARS-CoV-2 mRNA vaccines generate high neutralising antibodies (nAb) in most individuals, haematopoietic stem cell transplant (HSCT) and chimeric antigen receptor T-cell (CAR-T) recipients respond poorly. HSCT/CAR-T treatment ablates existing immune memory, with recipients requiring revaccination analogous to being vaccine naive. An optimal revaccination strategy for this cohort has not been defined. Factors predicting immunogenicity following three ancestral SARS-CoV-2 vaccines were assessed in 198 HSCT/CAR-T recipients and 96 healthcare workers (HCWs) recruited to multicentre studies. Only 25% of HSCT/CAR-T recipients generated nAbs following one dose, with titres 167-fold and 7-fold lower than that in HCWs after the first and second doses, respectively. Lower post-second dose nAb titres were associated with older age, rituximab use, and previous HSCT. ChAdOx1-S recipients were more likely to generate nAbs compared with mRNA vaccines, with titres comparable to HCWs. In contrast, nAbs were significantly lower in HSCT/CAR-T recipients than HCWs after mRNA vaccination. The poor first-dose immunogenicity in HSCT/CAR-T recipients suggests a minimum licensed dosing interval could limit the period of vulnerability following HSCT/CAR-T. The relative preservation of nAbs with ChAdOx1-S vaccination highlights the importance of evaluating alternative platforms to mRNA vaccination within this highly vulnerable clinical cohort.

Three-year survival follow-up of patients with gastrointestinal cancer treated during the COVID-19 pandemic in Spain: data from the PANDORA-TTD20 study.

The initial SARS-CoV-2 pandemic wave in Spain in 2020 precipitated significant paradigm shifts in gastrointestinal oncology patient management. This study captures the "Zeitgeist" of this period by analyzing adaptive strategies, treatment modifications, and survival outcomes, leveraging a 3-year follow-up perspective to extract insights from this unprecedented experience. We conducted a multicenter, retrospective cohort study utilizing the RETUD-TTD registry, encompassing 703 patients across 19 Spanish centers in April 2020. We evaluated alterations in clinical practice, therapeutic approaches, coronavirus disease 2019 (COVID-19)-related impacts, and patient survival. A Bayesian hierarchical model was employed to identify potential regional-specific frailties. The peak of the pandemic in April 2020 catalyzed substantial shifts in oncological care delivery. Outpatient consultations decreased by 13%, with a notable selection bias toward cases with more favorable prognostic indicators. Multidisciplinary tumor board discussions were significantly curtailed (eg, mean monthly colorectal cancer cases discussed was reduced from 40 to 23), compromising qualitative care measures. This occurred concurrently with an average of over 3 oncologists per center on medical leave. Contrary to initial concerns, the healthcare system demonstrated remarkable resilience. The majority of patients received standard-of-care therapies with regulatory approval, albeit with regimen modifications in 15% of cases. These adaptations included extended dosing intervals, dose intensity modulations, and transitions to oral formulations while maintaining unexpectedly stable long-term survival outcomes. The Bayesian frailty model detected minimal unmeasured prognostic factors related to geographic location, and the type of pandemic-induced adaptation did not significantly impact survival. The model revealed that coronavirus disease 2019's impact was less pronounced than other core prognostic variables. The decentralized Spanish healthcare system exhibited substantial robustness in managing pre-pandemic diagnosed gastrointestinal malignancies, despite asymmetrical, and occasionally severe organizational disruptions. The insights gleaned from this experience could inform future crisis preparedness strategies and optimize care provision during subsequent public health emergencies.

Future options for long-acting HIV treatment and prevention.

The aim of this review was to describe future options for long-acting HIV treatment and preexposure prophylaxis (PrEP) regimens featuring both innovations with currently approved antiretrovirals and a profile of investigational agents in the pipeline. Newer formulations and modes of delivery for existing antiretroviral drugs and a number of investigational agents are under study for long-acting HIV treatment and PrEP. Regimens with weekly oral dosing for HIV treatment, monthly oral dosing for HIV PrEP, and injectable agents with longer dosing intervals (every 3 months or longer) for treatment and PrEP are in clinical development. Newer agents with novel mechanisms of action and newer modes of administration including vaginal rings, implants, patches, and rectal douches also are under investigation. Despite the success of current antiretroviral therapy and PrEP with one-pill, once-daily regimens, there is a continuing need for new formulations, investigational agents, and novel modes of delivery to overcome barriers to implementation and ensure real-world effectiveness. Newer long-acting antiretroviral regimens for HIV treatment and PrEP using novel preparations and strategies will offer choice, enhance adherence, decrease toxicity, and improve patient and provider satisfaction.

Precision Dosing of Intravenous Tocilizumab: Development of Pharmacokinetic Model-Derived Tapering Strategies for Patients With Rheumatoid Arthritis.

Tocilizumab targets the interleukin-6 receptor, and dosing is complex owing to its nonlinear clearance related to target binding. Therefore, tapering tocilizumab requires a different approach than that of tumor necrosis factor inhibitors (TNFi). This study aimed to identify these differences and enable personalized treatment of rheumatoid arthritis (RA) beyond TNFi therapy. A population pharmacokinetic model of intravenous tocilizumab was developed using data from a randomized controlled trial of dose tapering in patients with RA. Subsequent population-level Monte Carlo and individual Bayesian simulations were performed to create tapering strategies involving dose reduction and interval extension. The target trough concentration of tocilizumab was 5 mg/L. Finally, the drug savings were compared between the 2 methods. The pharmacokinetic of tocilizumab was described with a 2-compartment model with parallel linear (CL 0.20 L/d) and nonlinear (VM 5.2 mg/d, KM 0.19 mg/L) elimination. The linear clearance rate and central volume of distribution increased with lean body mass, and men exhibited higher clearance rates than women. The simulated concentration-time profiles demonstrated that, owing to nonlinear clearance, drug concentrations decreased more than dose-proportionally with lower doses. Tapering based on an individual Bayesian approach emerged as the most promising strategy, yielding a 39% reduction in drug use across virtual populations. Tapering strategies were developed for intravenous tocilizumab, offering potential application in patients with RA who have reached low disease activity or remission, pending clinical validation. The developed strategies demonstrate that the tapering of tocilizumab should be approached more carefully and in smaller steps than that of TNFi.

Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial

BackgroundAfrican children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection.MethodsWe conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled.ResultsBetween January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls.ConclusionsWe found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection.Trial registrationISRCTN49726849 (registered on 27th October 2017).