Dataset Information

Pharmacodynamics of natalizumab extended interval dosing in MS.

ABSTRACT: OBJECTIVE:To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ. METHODS:In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and ?4-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints. RESULTS:Trough serum concentration was above the "therapeutic" concentration of 2.0 ?g/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ. CONCLUSIONS:Trough ?4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

SUBMITTER: Zhovtis Ryerson L

PROVIDER: S-EPMC7057061 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Pharmacodynamics of natalizumab extended interval dosing in MS.

Zhovtis Ryerson Lana L Li Xiaochun X Goldberg Judith D JD Hoyt Tamara T Christensen Angel A Metzger Ryan R RR Kister Ilya I Foley John J

Neurology(R) neuroimmunology & neuroinflammation 20200204 2

<h4>Objective</h4>To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ.<h4>Methods</h4>In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and α<sub>4</sub>-integrin rec ...[more]

PMID: 32019876

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Project description:ObjectivesTo review the evidence from controlled clinical trials of neonates given equal daily aminoglycoside doses as extended interval dosing (dosage interval typically 24 hours in term and 36-48 hours in immature neonates) compared with traditional dosing (dosage interval typically 8-12 hours in term and 12-24 hours in immature neonates).DesignSystematic review and meta-analysis of controlled trials found in electronic databases, trial registers, and references in reviews and selected trials.SettingsThe selected trials were blinded and assessed for methodological quality. Each trial's own predefined criteria for treatment failure, nephrotoxicity, ototoxicity, and therapeutic serum drug concentrations were used.SubjectsControlled trials of neonatal aminoglycoside treatment in which equal aminoglycoside daily doses were given at traditional and extended dosage intervals.Main outcome measuresSerum drug concentrations outside the therapeutic range. Treatment failure and toxicity.ResultsSixteen trials involving 823 neonates met the inclusion criteria for the systematic review. Twelve trials involving 698 neonates were included in the meta-analysis of the pharmacokinetics. Compared with traditional dosing, extended interval dosing was associated with a significantly lower risk of both peak (summary risk ratio 0.50, 95% confidence interval 0.26 to 0.94) and trough (0.36, 0.25 to 0.56) serum drug concentrations outside the therapeutic range. Accurate information on treatment failure was obtained in nine trials involving 555 neonates. One trial reported treatment failure. In this trial two neonates in the traditional dosing group did not respond to treatment within 72 hours. Nephrotoxicity was investigated in 589 neonates in 12 trials and ototoxicity in 210 neonates in four trials, with no significant differences between the two dosing regimens.ConclusionsExtended interval dosing of aminoglycosides in neonates is safe and effective, with a reduced risk of serum drug concentrations outside the therapeutic range.

Dataset Information

Pharmacodynamics of natalizumab extended interval dosing in MS.

Publications

Pharmacodynamics of natalizumab extended interval dosing in MS.

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