Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats

Byrnes-Blake, Kelly; Laurenzana, Elizabeth M.; Carroll, F. Ivy; Abraham, Philip; Gentry, W. Brooks; Landes, Reid D.; Owens, S. Michael

doi:10.1016/s0014-2999(03)01313-x

Cited by 65 publications

(84 citation statements)

References 13 publications

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“…In other words, AMP was formed at a rate that was faster than it was being eliminated (Figure 1). The characteristics of AMP elimination following a single METH dose in the rat have also been reported by several investigators (Byrnes-Blake et al 2003;Cho et al 2001;Milesi-Halle et al 2005;Riviere et al 2000). Milesi-Halle et al have reported a much lower AMP to METH ratio in the male and female rat following a 1 mg/kg IV dose (i.e., 0.29 and 0.22) when compared to the pigeon (i.e., 0.47 with an IV dose) (Milesi-Halle et al 2005).…”

Section: Discussionsupporting

confidence: 69%

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

Hendrickson

Hardwick

McMillan

et al. 2008

Pharmacology Biochemistry and Behavior

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Pigeons are used frequently as subjects in behavioral pharmacology research. An advantage of the pigeon is an exceedingly vascular breast muscle, which is easily accessible for injections. The purpose of these studies was to provide a profile of the pharmacokinetics of (+)-methamphetamine (METH) and (+)-amphetamine (AMP), a pharmacologically active metabolite, in pigeons (n = 6) after intramuscular (IM) and intravenous (IV) dosing (0.8 mg/kg). LC-MS/MS analysis was used to determine serum concentrations of METH and AMP. A modified crossover design was used to determine the bioavailability, time to maximum concentration, total clearance, the volume of distribution, the maximal concentration, the area under the concentration-time curve (AUC), and terminal elimination half-life for METH. The route of administration did not significantly affect these pharmacokinetic parameters. The time to maximum concentration for METH and AMP following IM administration was 0.3 h. Maximum AMP serum concentrations were achieved in 2 h, irrespective of the route of administration, and these concentrations remained essentially constant for an additional 6 h. The metabolism of METH to AMP was not affected by the route of administration, and the molar ratio AMP to METH AUC values were the same (IV=0.57; IM=0.41). These results show that METH pharmacokinetics after IM administration in the pigeon are similar to IV administration. Thus IM is a reasonable route of administration for METH behavioral assays in the pigeon if sufficient time for absorption is given following the dose, and the behavioral endpoint is not dependent on the rapid input of METH following an IV dose.

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Section: Discussionsupporting

confidence: 69%

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

Hendrickson

Hardwick

McMillan

et al. 2008

Pharmacology Biochemistry and Behavior

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“…[1][2][3][4][5] Anti-METH mAbs reside in the blood and extracellular fluid compartments where they bind METH with such high affinity that they rapidly redistribute METH from its sites of action in the brain and other organs into the blood stream. [6][7][8] MAbs offer specific advantages as a drug abuse therapy. Compared with other immunotherapies such as vaccines, mAbs necessarily do not require the function of the user's immune system to work, making them appropriate for immunosuppressed patients, including those with HIV/AIDS or autoimmune conditions.…”

Section: Introductionmentioning

confidence: 99%

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

Stevens

Henry

Owens

et al. 2014

mAbs

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This first-in-human study examined the safety and pharmacokinetics of ch-mAb7F9, an anti-methamphetamine monoclonal antibody, in healthy volunteers. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20 mg/kg were administered to 42 subjects who were followed for 147 d. Safety was measured by physical examinations, adverse events, vital signs, electrocardiograms, and clinical laboratory testing. Serum ch-mAb7F9 concentration and immunogenicity analyses were performed. There were no serious adverse reactions or discontinuations from the study due to adverse events. No trends emerged in the frequency, relatedness, or severity of adverse events with increased dose or between active and placebo treated subjects. Ch-mAb7F9 displayed expected IgG pharmacokinetic parameters, including a half-life of 17-19 d in the 3 highest dose groups and volume of distribution of 5-6 L, suggesting the antibody is confined primarily to the vascular compartment. Four (12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study; however, this response did not appear to be dose related. Overall, no apparent safety or tolerability concerns were identified; a maximum tolerated dose was not reached in this Phase 1 study. Ch-mAb7F9 therefore appears safe for human administration.

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“…These antibody medications reduce stimulant-induced locomotor activity (LMA) 1,2 and hemodynamic effects 3 in rats, and antagonize METH effects in pigeon drug discrimination 4 and rat selfadministration models. 5 Furthermore, anti-METH mAbs are effective when given before or after the METH is administered.…”

Section: Introductionmentioning

confidence: 99%

“…2 Anti-METH mAbs function via pharmacokinetic antagonism of METH effects. By dramatically altering the disposition of METH via high-affinity binding and redistribution, 1,6 they reduce its stimulant effects. 1,2 The binding interactions between METH and mAb are, however, complex.…”

Section: Introductionmentioning

confidence: 99%

“…By dramatically altering the disposition of METH via high-affinity binding and redistribution, 1,6 they reduce its stimulant effects. 1,2 The binding interactions between METH and mAb are, however, complex. Characterizing the factors that determine the efficacy of anti-drug antibodies continues to be a major goal of the development of these molecules as medications.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological effects of two anti-methamphetamine monoclonal antibodies

Laurenzana¹,

Stevens²,

Frank³

et al. 2014

Human Vaccines & Immunotherapeutics

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This lead candidate selection study compared two anti-(C)-methamphetamine (METH) monoclonal antibodies (mAb) to determine their ability to reduce METH-induced locomotor effects and redistribute METH and (C)-amphetamine (AMP) in a preclinical overdose model. Both mAbs have high affinity for METH, but mAb4G9 has moderate and mAb7F9 has low affinity for AMP. In the placebo-controlled behavioral experiment, the effects of each mAb on the locomotor response to a single 1 mg/kg intravenous (IV) METH dose were determined in rats. The doses of mAb binding sites were administered such that they equaled 1, 0.56, 0.32, and 0.1 times the molar equivalent (mol-eq) of METH in the body 30 min after the METH dose. METH disposition was determined in separate animals that similarly received either a 1 or 0.32 mol-eq dose of mAb binding sites 30 min after a 1 mg/kg METH dose. Total METH-induced distance traveled was significantly reduced in rats that received the highest three doses of each mAb compared with saline. The duration of METH effects was also significantly reduced by mAb7F9 at the highest dose. The disposition of METH was altered dose-dependently by both mAbs as shown in reductions of volume of distribution and total clearance, and increases in elimination half-life. These data indicate that both mAbs are effective at reducing METHinduced behavior and favorably altering METH disposition. Both were therefore suitable for further preclinical testing as potential human medications for treating METH use; however, due to results reported here and in later studies, mAb7F9 was selected for clinical development.

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Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats

Cited by 65 publications

References 13 publications

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

Bioavailability of (+)-methamphetamine in the pigeon following an intramuscular dose

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

Pharmacological effects of two anti-methamphetamine monoclonal antibodies

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