Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

BACKGROUND: Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. METHODS: We quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022, based on calendar-time proportional hazards models and matching approaches. RESULTS: We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR 1.66; 95% CI 1.07, 2.59; p = 0.02) after the first dose. CONCLUSIONS: Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. Here, we quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022. We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR: 1.66; 95% CI: 1.07, 2.59; p = 0.02) after the first dose. Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Population pharmacokinetic meta-analysis of five beta-lactams antibiotics to support dosing regimens in dogs for surgical antimicrobial prophylaxis.

The Pharmacokinetic/Pharmacodynamic (PK/PD) relationship of antimicrobial drugs (AMD) for surgical prophylaxis has been poorly studied, hampering evidence-based decision making around AMD dosing and timing. Our objective is to use PK/PD principles to inform (1) the timing of administration and (2) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cefalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. E. coli and methicillin-susceptible staphylococci were identified as possible intraoperative contaminants and their epidemiological cut-offs (ECOFF) were retrieved from the EUCAST database. Individual PK data were refitted with non-linear mixed effect models (Phoenix®). We performed Monte Carlo simulation to compute i) the 95th percentile of time of peak concentration in the peripheral compartment (informing timing between administration and first incision) and ii) the duration for which at least 90% of dogs maintain a free plasma concentration above ECOFF (informing timing of re-administration: 1.5-4 h). Cefazolin (22-25 mg/kg), cefuroxime (20 mg/kg), cefalexin (15 mg/kg) and amoxicillin (16.7 mg/kg) reached peak peripheral concentrations within 30 min, but ampicillin (20 mg/kg) required 82 min, respectively. For methicillin-susceptible staphylococci, cefazolin and cefuroxime require re-administration every 2 h, whereas cefalexin and both amoxicillin and ampicillin can be readministered every 3 and 4 h, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cefalexin failed uniformly. Alternatively, ampicillin and amoxicillin (critically ill dogs) may cover E. coli contaminations, but only if readministered every 1.5 h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing.

A multiprovincial retrospective analysis of the incidence of myocarditis or pericarditis after mRNA vaccination compared to the incidence after SARS-CoV-2 infection.

Objective: To compare myocarditis/pericarditis risk after COVID-19 mRNA vaccination versus SARS-CoV-2 infection, and to assess if myocarditis/pericarditis risk varies by vaccine dosing interval. Methods: In this retrospective cohort study, we used linked databases in Quebec, Ontario, and British Columbia between January 26, 2020, and September 9, 2021. We included individuals aged 12 or above who received an mRNA vaccine as the second dose or were SARS-CoV-2-positive by RT-PCR. The outcome was hospitalization/emergency department visit for myocarditis/pericarditis within 21 days of exposure. We calculated age- and sex-stratified incidence ratios (IRs) of myocarditis/pericarditis following mRNA vaccination versus SARS-CoV-2 infection. We also calculated myocarditis/pericarditis incidence by vaccine type, homologous/heterologous schedule, and dosing interval. We pooled province-specific estimates using meta-analysis. Results: Following 18,860,817 mRNA vaccinations and 860,335 SARS-CoV-2 infections, we observed 686 and 160 myocarditis/pericarditis cases, respectively. Myocarditis/pericarditis incidence was lower after vaccination than infection (IR [BNT162b2/SARS-CoV-2], 0.14; 95%CI, 0.07-0.29; IR [mRNA-1273/SARS-CoV-2], 0.28; 95%CI, 0.20-0.39). Within the vaccinated cohort, myocarditis/pericarditis incidence was lower with longer dosing intervals; IR (56 or more days/15-30 days) was 0.28 (95%CI, 0.19-0.41) for BNT162b2 and 0.26 (95%CI, 0.18-0.38) for mRNA-1273. Conclusion: Myocarditis/pericarditis risk was lower after mRNA vaccination than SARS-CoV-2 infection, and with longer intervals between primary vaccine doses.

A comparison of clinical outcomes associated with dosing metronidazole every 8 hours versus every 12 hours: a systematic review and metaanalysis.

Background: Metronidazole treats obligate anaerobic bacterial and protozoal infections, with an elimination half-life of around 8 hours. The long elimination half-life, the favorable ratio of steady-state serum levels to minimum inhibitory concentration, and the presence of active metabolites have led to the consideration of metronidazole use at 12-hour dosage intervals. This systematic review aimed to compare the clinical outcomes of twice-daily and thrice-daily metronidazole dosing. Methods: Using the PRISMA checklist, we searched five databases to systematically identify all relevant studies published up to June 16, 2023. Results: The final analysis included two published retrospective cohort studies of hospitalized adult patients: a single site study (n = 200) and a multisite study (n = 85) of "good" quality, as measured by the Newcastle-Ottawa scale. The reported baseline characteristics of the 8-hour and 12-hour dosing groups were comparable, and neither study identified significant differences in primary and secondary clinical outcomes. Metaanalysis of the need to escalate antibiotic therapy also showed no statistically significant differences using the Mantel-Haenszel fixed-effect method (95% confidence interval: 47.6% lower to 6.4 times higher risk, P = 0.34) and inverse-variance method (risk ratio: 1.87; 95% confidence interval: 0.52-6.65, P = 0.34). Conclusions: This review suggests that dosing metronidazole every 12 hours is as effective as every-8-hour dosing for hospitalized patients with anaerobic infections. These encouraging findings would benefit from validation by a multicenter randomized controlled trial since there would be many benefits to a 12-hour dosing interval while achieving similar clinical outcomes with traditional dosing. The studies in this systematic review excluded patients with Clostridioides difficile and central nervous system and amebiasis infections, so the findings do not apply to these infection types.

Incidence of serious adverse events caused by tyrosine kinase inhibitor treatment following immune checkpoint inhibitor therapy in advanced NSCLC patients with oncogenic driver alterations.

BACKGROUND: Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown. METHODS: We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0. RESULTS: Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7-698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3 months after ICIs than in patients (n = 23) who initiated TKI treatment 3 months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55). CONCLUSION: The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs.

Extending the dosing interval of COVID-19 vaccination leads to higher rates of seroconversion in people living with HIV.

Introduction: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an effective way of protecting individuals from severe coronavirus disease 2019 (COVID-19). However, immune responses to vaccination vary considerably. This study dynamically assessed the neutralizing antibody (NAb) responses to the third dose of the inactivated COVID-19 vaccine administered to people living with human immunodeficiency virus (HIV; PLWH) with different inoculation intervals. Methods: A total of 171 participants were recruited: 63 PLWH were placed in cohort 1 (with 3-month interval between the second and third doses), while 95 PLWH were placed in cohort 2 (with 5-month interval between the second and third doses); 13 individuals were enrolled as healthy controls (HCs). And risk factors associated with seroconversion failure after vaccination were identified via Cox regression analysis. Results: At 6 months after the third vaccination, PLWH in cohort 2 had higher NAb levels (GMC: 64.59 vs 21.99, P < 0.0001) and seroconversion rate (68.42% vs 19.05%, P < 0.0001). A weaker neutralizing activity against the SARSCoV-2 Delta variant was observed (GMT: 3.38 and 3.63, P < 0.01) relative to the wildtype strain (GMT: 13.68 and 14.83) in both cohorts. None of the participants (including HCs or PLWH) could mount a NAb response against Omicron BA.5.2. In the risk model, independent risk factors for NAb seroconversion failure were the vaccination interval (hazed ration [HR]: 0.316, P < 0.001) and lymphocyte counts (HR: 0.409, P < 0.001). Additionally, PLWH who exhibited NAb seroconversion after vaccination had fewer initial COVID-19 symptoms when infected with Omicron. Discussion: This study demonstrated that the third vaccination elicited better NAb responses in PLWH, when a longer interval was used between vaccinations. Since post-vaccination seroconversion reduced the number of symptoms induced by Omicron, efforts to protect PLWH with risk factors for NAb seroconversion failure may be needed during future Omicron surges. Clinical trial registration: https://beta.clinicaltrials.gov/study/NCT05075070, identifier NCT05075070.

Optimal Administration of Glycyrrhizin Avoids Pharmacokinetic Interactions With High-dose Methotrexate and Exerts a Hepatoprotective Effect.

BACKGROUND/AIM: Glycyrrhizin (GZ) is widely used to treat high-dose methotrexate (MTX)-induced liver dysfunction. However, in a previous in vivo study, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries. In this study, we investigated the optimal dosing interval in rats to avoid the interaction between high-dose MTX and GZ and to demonstrate the inherent hepatoprotective effect of GZ. MATERIALS AND METHODS: Male Wistar rats were treated with high-dose MTX (2,000 mg/kg) alone, with concomitant administration of 100 mg/kg GZ or GZ administered 3, 6, and 24 h before MTX administration. Plasma concentrations of MTX, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. RESULTS: The plasma concentration and half-life of methotrexate were significantly increased after concomitant administration of GZ, or when GZ was administered 3 h before MTX administration, compared with MTX alone, increasing hepatic enzyme levels. However, when GZ was administered 6 and 24 h before MTX administration, the levels were not significantly different from those of MTX alone and showed a tendency to decrease MTX-induced liver injury. These results suggest that the pharmacokinetic interaction between GZ and MTX could be avoided and the hepatoprotective effect of GZ could be achieved by an optimal dosing regimen, using the half-life of GZ as an indicator. CONCLUSION: When using high-dose MTX in combination with GZ, the administration intervals should be considered to avoid unwanted interactions and to achieve the GZ hepatoprotective effect.

Determining the Optimal SARS-CoV-2 mRNA Vaccine Dosing Interval for Maximum Immunogenicity.

OBJECTIVE: Emerging evidence indicates that longer SARS-CoV-2 vaccine dosing intervals results in an enhanced immune response. However, the optimal vaccine dosing interval for achieving maximum immunogenicity is unclear. METHODS: This study included samples from adult paramedics in Canada who received two doses of either BNT162b2 or mRNA-1273 vaccines and provided blood samples six months (170 to 190 days) after the first vaccine dose. The main exposure variable was vaccine dosing interval (days), categorized as "short" (first quartile), "moderate" (second quartile), "long" (third quartile), and "longest" interval (fourth quartile). The primary outcome was total spike antibody concentrations, measured using the Elecsys SARS-CoV-2 total antibody assay. Secondary outcomes included spike and receptor-binding domain (RBD) immunoglobulin G (IgG) antibody concentrations, and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to wild-type spike protein and several different Delta variant spike proteins. We fit a multiple log-linear regression model to investigate the association between vaccine dosing intervals and the antibody concentrations. RESULTS: A total of 564 adult paramedics (mean age 40 years, SD=10) were included. Compared to "short interval" (≤30 days), vaccine dosing intervals of the long (39-73 days) group (ß= 0.31, 95% Confidence interval (CI): 0.10-0.52) and the longest (≥74 days) group (ß = 0.82. 95% CI: 0.36-1.28) were associated with increased spike total antibody concentration. Compared to the short interval, the longest interval quartile was associated with higher spike IgG antibodies, while the long and longest intervals were associated with higher RBD IgG antibody concentrations. Similarly, the longest dosing intervals increased inhibition of ACE-2 binding to viral spike protein. CONCLUSION: Increased mRNA vaccine dosing intervals longer than 38 days result in higher levels of anti-spike antibodies and ACE-2 inhibition when assessed six months after the first COVID-19 vaccine.

The immunogenicity of an extended dosing interval of BNT162b2 against SARS-CoV-2 Omicron variant among healthy school-aged children, a randomized controlled trial.

OBJECTIVES: To evaluate the immunogenicity of an extended interval regimen of BNT162b2 among healthy school-age children. METHODS: A randomized-control trial conducted among healthy Thai children aged 5-11 years. Participants received two doses of BNT162b2 with an 8-week (extended dosing) vs 3-week interval. Immunogenicity was determined by neutralization test (NT) against the Omicron variant, surrogate virus NT (sVNT; BA.1, % inhibition), and pseudovirus NT (BA.2, the half-maximal inhibition dilution or ID50). The third dose was offered to participants who had sVNT <68% inhibition. The immunogenicity outcome was evaluated at 14 days after the second and third doses. RESULTS: During February to April 2022, 382 children with a median age (interquartile range) of 8.4 years (6.6-10.0) were enrolled. At 14 days, after two doses of BNT162b2, the geometric means of sVNT in 8-week vs 3-week interval groups were 49.6 (95% confidence interval [CI] 44.8-54.9) vs 16.5 (95% CI 13.0-20.9), with a geometric means ratio of 3.0 (95% CI 2.4-3.8). Among 102 participants who received the third dose at a median of 15 weeks from the second dose, the geometric means of sVNT increased to 73.3 (95% CI 69.0-77.8) and pseudovirus NT increased to 326 (95% CI 256-415). CONCLUSION: The extended 8-week interval regimen of BNT162b2 induced higher neutralizing antibodies than a standard 3-week interval regimen. The third dose induced high neutralizing antibodies against the Omicron variant.

Natalizumab wearing-off symptoms: effect of extend interval dosing during Sars-CoV-2 pandemic.

BACKGROUND: Many patients treated with Natalizumab experience wearing-off symptoms (WoS) towards the end of the administration cycle. During the pandemic we advised and asked patients undergoing treatment with Natalizumab if they wanted to be shifted from a standard interval dosing (StID of 4 weeks) to an extended interval dosing (ExID of 5-6 weeks), regardless of their JCV index. Our main objective was to study prevalence and incidence of WoS when ExID was adopted. METHODS: We enrolled 86 patients, from May 2020 to January 2021, evaluated at baseline and during a 6 months follow-up with a survey focused on WoS, Fatigue Severity Scale (FSS), Expanded Disability Status Scale (EDSS) and MRI. RESULTS: Among the 86 patients, 32 (37.2%) reported WoS. Most common one was fatigue (93.7%). Mean EDSS was higher in the group reporting WoS (3.8 WoS vs 3.1 non-WoS, p < 0.05). Sphincterial function was the EDSS item that significantly differed between the WoS group and the non-WoS group (1.4 WoS vs 0.6 non-WoS, p < 0.001). WoS correlate with the FSS scale (p < 0.001). CONCLUSION: Adopting an extended interval dosing does not result in significantly different occurrence of WoS between the ExID and the StID populations, in our cohort of patients. Interestingly, there is a strong correlation between WoS and a higher EDSS and FSS. Safety and efficacy of Natalizumab with ExID are relatively preserved in our study.

Real-World nivolumab dosing patterns and safety outcomes in patients receiving adjuvant therapy for melanoma.

BACKGROUND: Nivolumab at a dose of 480 mg every 4 weeks (Q4W) is approved for the adjuvant treatment of melanoma. However, real-world data on this regimen are limited in this setting. METHODS: This retrospective observational study utilized data from the US Oncology Network iKnowMed electronic health record database and patient medical charts. Eligible patients were diagnosed with melanoma and received adjuvant nivolumab monotherapy from March to August 2018. Patients were grouped by dosing regimen: cohort 1 (C1), de novo nivolumab 480 mg Q4W; cohort 2 (C2), switched to nivolumab 480 mg Q4W after nivolumab 240 mg or 3 mg/kg every 2 weeks (Q2W); cohort 3 (C3), de novo nivolumab 3 mg/kg Q2W; or cohort 4 (C4), de novo nivolumab 240 mg Q2W. Patients were followed for up to 12 months. Duration of therapy and safety/tolerability were assessed. RESULTS: One hundred ninety-one patients were included (C1, n = 40; C2, n = 74; C3, n = 22; C4, n = 55). Duration of therapy was relatively consistent across cohorts (median, 10.3 months; range, 8.3-10.7). Likewise, proportions of patients experiencing treatment-related adverse events (TRAEs) were similar (range, 54.5%-60.1%), as were the most common events (fatigue, rash, diarrhea, hypothyroidism, nausea, and pruritus). However, proportions experiencing 'significant' TRAEs varied between cohorts. Proportions discontinuing treatment were relatively consistent across cohorts. Propensity score matching and sensitivity analyses generally supported the unadjusted findings. CONCLUSIONS: Real-world safety profiles of nivolumab 240 mg Q2W and 480 mg Q4W were similar, and both were comparable to the well-documented safety of weight-based dosing (3 mg/kg Q2W), further supporting their approval and use in the adjuvant setting for melanoma.

Altering the mRNA-1273 dosing interval impacts the kinetics, quality, and magnitude of immune responses in mice.

For a vaccine to achieve durable immunity and optimal efficacy, many require a multi-dose primary vaccination schedule that acts to first "prime" naive immune systems and then "boost" initial immune responses by repeated immunizations (ie, prime-boost regimens). In the context of the global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 2-dose primary vaccination regimens were often selected with short intervals between doses to provide rapid protection while still inducing robust immunity. However, emerging post-authorization evidence has suggested that longer intervals between doses 1 and 2 for SARS-CoV-2 vaccines may positively impact robustness and durability of immune responses. Here, the dosing interval for mRNA-1273, a messenger RNA based SARS-CoV-2 vaccine administered on a 2-dose primary schedule with 4 weeks between doses, was evaluated in mice by varying the dose interval between 1 and 8 weeks and examining immune responses through 24 weeks after dose 2. A dosing interval of 6 to 8 weeks generated the highest level of antigen-specific serum immunoglobulin G binding antibody titers. Differences in binding antibody titers between mRNA-1273 1 µg and 10 µg decreased over time for dosing intervals of ≥4 weeks, suggesting a potential dose-sparing effect. Longer intervals (≥4 weeks) also increased antibody-dependent cellular cytotoxicity activity and numbers of antibody-secreting cells (including long-lived plasma cells) after the second dose. An interval of 6 to 8 weeks elicited the strongest CD8+ T-cell responses, while an interval of 3 weeks elicited the strongest CD4+ T-cell response. Overall, these results suggest that in a non-pandemic setting, a longer interval (≥6 weeks) between the doses of the primary series for mRNA-1273 may induce more durable immune responses.

No increase of serum neurofilament light in relapsing-remitting multiple sclerosis patients switching from standard to extended-interval dosing of natalizumab.

BACKGROUND: Accumulating evidence supports the efficacy of administering natalizumab (NZ) with extended-interval dosing (EID) in patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: We switched NZ dosing from 4-week to 6-week intervals in patients with RRMS, and investigated the effect on serum neurofilament light chain (sNfL) concentrations. METHODS: We included two cohorts of patients with RRMS treated with NZ: one received the standard-interval dosing (4 weeks) at baseline, and were switched to 6-week intervals (EID4-6, N = 45). The other cohort received EID (5- or 6-week intervals) both at baseline and during follow-up (EID5/6, N = 25). Serum samples were collected in the EID4-6 cohort at every NZ infusion, for 12 months. The primary outcome was the change in sNfL concentrations after switching to EID. RESULTS: The baseline mean sNfL concentration in the EID4-6 cohort was 10.5 ng/L (standard deviation (SD) = 6.1), and it remained unchanged at 12 months. Moreover, individual sNfL concentrations did not change significantly after extending the NZ dosing intervals. In addition, the EID4-6 and EID5/6 cohorts had similar baseline sNfL concentrations. CONCLUSION: We concluded that extending the NZ dosing interval did not increase axonal damage, as determined with sNfL, in patients with RRMS.

Adherence to the Recommended HPV Vaccine Dosing Schedule among Adolescents Aged 13 to 17 Years: Findings from the National Immunization Survey-Teen, 2019-2020.

The 9-valent human papillomavirus (9-vHPV) vaccine uptake rate among adolescents has improved over the years; however, little is known about the adherence to the recommended dosing schedule. This study examines the prevalence and factors associated with adherence to the recommended 9vHPV vaccination dosing schedule among adolescents aged 13 to 17 years. The cross-sectional study was conducted using the 2019-2020 National Immunization Survey-Teen. The parents of 34,619 adolescents were included in our analyses. The overall up-to-date (UTD) prevalence was 57.1%. The UTD prevalence was 60.0% among females and 54.2% among males. Adolescents aged 16 years had the highest UTD prevalence of 63.0%. The UTD prevalence was 61.6% among Hispanics and 54.7% among non-Hispanic Whites. Overall, compared to females, males had 14% lower odds of UTD. The odds of UTD were 1.91 times, 2.08 times, and 1.98 times higher among adolescents aged 15-17 years, respectively, compared to those aged 13 years. Moreover, region, poverty, insurance status, mothers' educational level, and provider recommendation were associated with UTD. Our findings show that adherence to the recommended 9vHPV vaccine schedule is low in the US. Targeted public health efforts are needed to improve the rates of adherence to the recommended 9vHPV dose schedule.

Immune checkpoint-targeted antibodies: a room for dose and schedule optimization?

Anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors are therapeutic monoclonal antibodies that do not target cancer cells but are designed to reactivate or promote antitumor immunity. Dosing and scheduling of these biologics were established according to conventional drug development models, even though the determination of a maximum tolerated dose in the clinic could only be defined for anti-CTLA-4. Given the pharmacology of these monoclonal antibodies, their high interpatient pharmacokinetic variability, the actual clinical benefit as monotherapy that is observed only in a specific subset of patients, and the substantial cost of these treatments, a number of questions arise regarding the selected dose and the dosing interval. This review aims to outline the development of these immunotherapies and considers optimization options that could be used in clinical practice.

Penetration of topically administered dexamethasone disodium phosphate and prednisolone acetate into the normal equine ocular fluids.

BACKGROUND: Topical dexamethasone and prednisolone are currently the mainstay treatment for equine ophthalmic inflammatory diseases, such as equine recurrent uveitis. Comparative pharmacokinetic studies in horses are lacking and current guidelines are mainly based on empirical data and extrapolation from other species. OBJECTIVES: To investigate the penetration and local concentrations of topically applied dexamethasone and prednisolone in normal equine ocular fluids and serum. STUDY DESIGN: Prospective randomised experimental pharmacokinetic study. METHODS: Twenty-one Shetland ponies without ophthalmic disease were treated bilaterally topically every 2 hours during 24 hours to obtain steady state drug concentrations. One eye was treated with 0.15 mg of dexamethasone disodium phosphate (0.1%), and the other eye was simultaneously treated with 1.5 mg of prednisolone acetate (1%). Serum samples were taken prior to the induction of general anaesthesia. Aqueous and vitreous humour samples were taken during euthanasia at time points after administration of the last dose (t = 5 min, t = 15 min, t = 30 min, t = 60 min, t = 90 min, t = 120 min, t = 180 min). Each pony was randomly assigned to one time point, and three ponies were sampled per time point. Dexamethasone and prednisolone concentrations were measured by liquid chromatography-mass spectrometry. RESULTS: The mean dexamethasone concentration in aqueous humour was 32.4 ng/mL (standard deviation [SD] 10.9) and the mean prednisolone concentration was 321.6 ng/mL (SD 96.0). In the vitreous and in serum samples concentrations of both corticosteroids were below the limit of detection (LOD 2.5 ng/mL). MAIN LIMITATIONS: The study group was limited to subjects without evidence of current ophthalmic disease. A limited number of time points were measured. CONCLUSIONS: Potentially effective dexamethasone and prednisolone concentrations were measured in the anterior chamber, but vitreal concentrations were negligible. Systemic uptake was low. Therefore, treatment with only topically administered corticosteroids is deemed insufficient in horses in cases of posterior uveitis. Further studies evaluating other routes of administration are warranted.

Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.

A randomized study of natalizumab dosing regimens for relapsing-remitting multiple sclerosis.

BACKGROUND: REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing-remitting multiple sclerosis (RRMS) patients. OBJECTIVE: To examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients. METHODS: Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60. RESULTS: In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable. CONCLUSION: Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.