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. 2021 Feb;11(1):182-191.
doi: 10.1007/s13346-020-00758-9.

An injectable microparticle formulation for the sustained release of the specific MEK inhibitor PD98059: in vitro evaluation and pharmacokinetics

Youssef W Naguib  1   2 , Brittany E Givens  1   3 , Giang Ho  1 , Yang Yu  4 , Shun-Guang Wei  4   5   6 , Robert M Weiss  4 , Robert B Felder  4   7   6 , Aliasger K Salem  8   9
Affiliations

An injectable microparticle formulation for the sustained release of the specific MEK inhibitor PD98059: in vitro evaluation and pharmacokinetics

Youssef W Naguib et al. Drug Deliv Transl Res. 2021 Feb.

Abstract

PD98059 is a reversible MEK inhibitor that we are investigating as a potential treatment for neurochemical changes in the brain that drive neurohumoral excitation in heart failure. In a rat model that closely resembles human heart failure, we found that central administration of PD98059 inhibits phosphorylation of ERK1/2 in the paraventricular nucleus of the hypothalamus, ultimately reducing sympathetic excitation which is a major contributor to clinical deterioration. Studies revealed that the pharmacokinetics and biodistribution of PD98059 match a two-compartment model, with drug found in brain as well as other body tissues, but with a short elimination half-life in plasma (approximately 73 min) that would severely limit its potential clinical usefulness in heart failure. To increase its availability to tissues, we prepared a sustained release PD98059-loaded PLGA microparticle formulation, using an emulsion solvent evaporation technique. The average particle size, yield percent, and encapsulation percent were found to be 16.73 μm, 76.6%, and 43%, respectively. In vitro drug release occurred over 4 weeks, with no noticeable burst release. Following subcutaneous injection of the microparticles in rats, steady plasma levels of PD98059 were detected by HPLC for up to 2 weeks. Furthermore, plasma and brain levels of PD98059 in rats with heart failure were detectable by LC/MS, despite expected erratic absorption. These findings suggest that PD98059-loaded microparticles hold promise as a novel therapeutic intervention countering sympathetic excitation in heart failure, and perhaps in other disease processes, including cancers, in which activated MAPK signaling is a significant contributing factor. Graphical abstract.

Keywords: Heart failure; LC/MS; MEK1/2 inhibitor; Microparticles; PD98059; Sustained release.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1:
Figure 1:
Characterization of the prepared PD98059-loaded PLGA microparticles. (a) Scanning electron microscopy (SEM) image of the drug-loaded microparticles. (b) Particle size distribution, measured by ImageJ analysis of 100 particles in SEM images. (c) Differential scanning calorimetry (DSC) thermograms of PD98059 (green), PLGA (black), a physical mixture of the two (blue), and PD98059-loaded microparticles (red). (d) In vitro release profile of PD98059 from PLGA microparticles (data represent mean ± SD, n=3).
Figure 2:
Figure 2:
(a) Plasma PD98059 levels vs. time (n=3 for all time points, except 6 h, which has n=1) and (b) organ levels of PD98059 (data represent mean ± SD, n=3) following IV injection of 1 mg of PD98059 dissolved in 10% w/v Tween 80 aqueous solution in healthy rats.
Figure 3:
Figure 3:
Comparison of Plasma PD98059 levels vs. time curves following IV injection of PD98059 and SC injection of PD98059-loaded PLGA microparticles (data represent mean ± SD, n=3). AUC0-t calculations were based on non-compartmental analysis (NCA) using PK Solver ad-in.
Figure 4:
Figure 4:
Plasma and brain PD98059 levels vs. time following the SC injection of 3.6 mg of PD98059 in PD98059-loaded PLGA microparticles in rats with heart failure (data represent mean ± SD, n=2–3).
See this image and copyright information in PMC

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