A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice

Abstract

Aims A recombinant humanized anti-cocaine monoclonal antibody (mAb), h2E2, is at an advanced stage of pre-clinical development as an immunotherapy for cocaine abuse. It is hypothesized that h2E2 binds to and sequesters cocaine in the blood. Main Methods A three-compartment model of the effects of h2E2 on cocaine's distribution was constructed. The model assumes that h2E2 binds to cocaine and that the h2E2-cocaine complex does not enter the brain but distributes between the central and peripheral compartments. Free cocaine is eliminated from both the central and peripheral compartments, and h2E2 and the h2E2-cocaine complex are eliminated from the central compartment only. This model was tested against a new dataset measuring cocaine concentrations in the brain and plasma over one hour in the presence and absence of h2E2. Key findings The mAb significantly increased plasma cocaine concentrations with a concomitant significant decrease in brain concentration. Plasma concentrations declined over the 1-hour sampling period in both groups. With a set of parameters within reasonable physiological ranges, the three-compartment model was able to qualitatively and quantitatively simulate the increased plasma concentration in the presence of the antibody and the decreased peak brain concentration in the presence of antibody. Importantly, the model explained the decline in plasma concentrations over time as distribution of the cocaine-h2E2 complex into a peripheral compartment. Significance This model will facilitate the targeting of ideal mAb PK/PD properties thus accelerating the identification of lead candidate anti-drug mAbs.

Selected Abstracts from Pharmacology 2019

“…The drastic inhibition of carboxylesterase-mediated metabolism of cocaine in the presence of the antibody is consistent with h2E2 acting as a chemical antagonist of cocaine. The seemingly paradoxical elimination of cocaine from the plasma in the presence of h2E2 in vivo may be resolved by investigating whether the observed decline in plasma concentration actually represents a slowed distribution phase (Wetzel et al, 2017 Formulation 2 while the same results against fungus, that is, Formulation 1 (4.5-cm ZI against rust while 5.0-cm against smut) was more effective than Formulation 2 (3.00-cm ZI against rust and 3.5-cm ZI against smut). Phytochemical analysis showed that garlic has organosulfur compounds (11-35 mgÁg −1 of fresh garlic), arginine, oligosaccharides, flavonoids, and selenium.…”

If there were an effective pharmacotherapy for cocaine use disorder, what would it do?

“…Shoptaw et al [7] note the development of a recombinant humanized anti-cocaine monoclonal antibody [8] as a promising way forward. Particularly long-acting agents may offer a more sustainable model of care.…”

“…Nascent efforts in the field carry potential for success. One notable example involves medication development for cocaine overdose, a monoclonal antibody that sequesters cocaine in circulating blood [8]. An effective overdose medication would have significant health impact, an effect that perhaps could be boosted when co‐administered with an opioid reversal agent in emergency settings and with an overdose of opioids and/or cocaine.…”

Ligand binding to a humanized anti-cocaine mAb detected by non-reducing SDS-PAGE

“…In addition to functional studies in rats and mice [ [2] , [3] , [4] , [5] ], our laboratory has also performed many structural and binding studies, using a variety of techniques [ 6 , 7 ]. We developed a method for measuring ligand binding by intrinsic mAb fluorescence quenching [ 8 ], as well as by ligand stabilization against thermal denaturation, using extrinsic fluorescent dyes and the differential scanning fluorimetry (DSF) method [ 9 ].…”