Biomedical subjects

Berend Neuteboom

Publications and source records attributed to Berend Neuteboom.

3 recordsLinked to original sources

PubMed2005

Interferon beta-1a overdose in a multiple sclerosis patient.

OBJECTIVE: To report on a patient with multiple sclerosis (MS) who attempted suicide by taking an overdose of interferon (IFN) beta-1a. CASE SUMMARY: A 38-year-old man with MS and depressive symptoms self-administered approximately 6 or 7 prefilled syringes containing 44 mug (12 MIU) of subcutaneous IFN beta-1a in a suicide attempt. Clinical examination in the emergency department revealed a modest rise in body temperature and diffuse redness of the skin of the limbs and truncal region. The patient's signs and symptoms resolved over the following 24 hours. IFN beta-1a was temporarily withdrawn and treatment with citalopram, which the patient had spontaneously discontinued before the suicide attempt, was resumed. Laboratory assessment showed no modifications in biochemical and hematologic parameters. The IFN beta-1a concentration in the serum sample taken at 48 hours after the suicide attempt confirmed that the patient had taken a very high dose of IFN. DISCUSSION: Depression, a common condition in MS patients, was precipitated in this patient by the spontaneous discontinuation of citalopram and not influenced by IFN beta-1a therapy, which the patient resumed at 44 mug 3 times per week. CONCLUSIONS: This case demonstrates the risks of depression in MS patients and the danger of discontinuing treatment with antidepressants. This report also shows that approximately 264-308 mug of IFN beta-1a, the highest single dose of IFN beta-1a reported taken by a human as of this writing, caused only a transient and self-limiting malaise.

Adult↗

PubMed2005

Pharmacokinetics and pharmacodynamics of PEGylated IFN-beta 1a following subcutaneous administration in monkeys.

PURPOSE: To characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of a new polyethylene glycol (PEG) conjugate formulation of interferon (IFN)-beta la following subcutaneous (SC) administration in monkeys. METHODS: Single SC injections of 0.3, 1, and 3 million international units (MIU)/kg of PEG-IFN-beta 1a were administered to 3 groups of cynomolgus monkeys (n = 4 each). Plasma concentrations of drug and neopterin, a classic biomarker for IFN-beta PD, were measured at various time-points after dosing. PK/PD profiles were described by noncompartmental methods and pooled data by an integrated mathematical model, where fixed and delayed concentration-time profiles were used as driving functions in an indirect stimulatory response model. RESULTS: PEG-IFN-beta 1a was rapidly absorbed, with peak concentrations observed at about 4-5 h. Compared to previous identical SC doses of IFN-beta la, administration of 1 and 3 MIU/kg of pegylated drug resulted in 27- and 16-fold increases in area under the concentration-time curves. Neopterin concentrations followed a typical dose-dependent biphasic pattern. Pooled PD profiles were well-described by the PK/PD model, and the neopterin elimination rate (0.0190 h(-1)) is consistent with previous estimates. CONCLUSIONS: The PEG-modification of IFN-beta la provides enhanced drug exposure and similar pharmacodynamics of neopterin compared to the unmodified formulation.

2',5'-Oligoadenylate Synthetase↗

PubMed2003

Receptor-mediated pharmacokinetics and pharmacodynamics of interferon-beta1a in monkeys.

A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to simultaneously characterize interferon after i.v. and s.c. dosing at various dose levels. A sequential study in monkeys (n = 18) was conducted, where single doses of 1, 3, and 10 MIU/kg of recombinant-human interferon-beta (IFN-beta) 1a were given i.v. and then s.c. Plasma concentrations of IFN-beta were determined and biphasic neopterin concentrations were used as the pharmacodynamic (PD) endpoint. Multiple dosing also was evaluated by giving 1 MIU/kg s.c. doses once daily for 7 days (n = 3). The integrated model uses target-mediated drug disposition to describe drug elimination by receptor binding and internalization, and well characterizes the observed nonlinear pharmacokinetic (PK) profiles. The s.c. doses exhibited an absorption phase (Tmax = 3 h) and incomplete bioavailability (F = 0.3-0.7). An indirect response model for stimulation of neopterin triphosphate production by activated receptor complex followed by conversion to neopterin was used to jointly model the formation and loss of neopterin with a capacity factor Smax = 23.8. Greater relative neopterin response after s.c. dosing was accounted for by prolonged receptor activation relative to the SC50 value. Repeated daily s.c. dosing produced modestly elevated IFN-beta1a concentrations and neopterin concentrations that were lower than simulated from single-dose modeling. Although several mechanisms could be involved, these phenomena were simply remodeled as down-regulation of Smax and receptors. The PK/PD model for IFN-beta1a depicts receptor binding as a key feature controlling nonlinear elimination, nonstationary kinetics, and neopterin induction in a manner consistent with known processes controlling its disposition and pharmacological effects.

Animals↗