Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats

Hadeel A. Khalil, Mohammed A. W. ElKhatib, Tarek S. Belal, Ahmed F. El-Yazbi, Dalia A. Hamdy
2017 Drugs in RD  
Objectives Co-administration of posaconazole (PSZ) and vincristine (VCR) in the treatment of patients with acute lymphoblastic leukemia increases the neurotoxicity of VCR. Our aim is to study the effect of increased lipoprotein levels on the pharmacokinetics of PSZ and VCR upon co-administration in rats. Methods Rats were assigned to three groups, normolipidemic (NL), intermediate hyperlipidemic (IHL), and extreme hyperlipidemic (HL) groups. All rats were administered PSZ orally followed by VCR
more » ... intravenously 4 h later. For the pharmacokinetic study, serial plasma samples were collected over 96 h and for tissue distribution study; plasma, lung, and liver tissues were collected over 48 h post oral dosing. Results Posaconazole showed higher plasma concentrations than VCR at all time points. Co-administration of VCR with PSZ reduced PSZ weight normalized oral clearance, increased PSZ area under the plasma concentration-time curve (AUC) from time zero to infinity, showed higher PSZ liver concentrations, and increased VCR volume of distribution of the central compartment. Upon increasing the lipoprotein levels, PSZ showed higher plasma availability and delayed tissue distribution, whereas VCR had shown a significant decrease in PSZ AUC 0-24h , AUC 0-tlast , and AUC o-inf (NL = IHL [ HL) and a significant increase in the volume of distribution (NL = IHL \ HL). Vincristine has shown higher tissue uptake and concentrations. Conclusion Monitoring cholesterol and triglyceride levels in patients with acute lymphoblastic leukemia is advisable to decrease VCR neurological side effect incidences and delay the activity of both PSZ and VCR. Key Points Hyperlipidimia alone resulted in alterations of PSZ PK and delayed its onset of activity but had no effect on VCR PK when each drug was administered alone. Coadministration of both drugs in NL rats decreased PSZ Cl/f and increased its plasma and liver availability whereas, it increased VCR unbound fraction and tissue distribution. Coadministration of both drugs in HL rats further delayed PSZ tissue distribution and thus its assumed onset of action and decreased the plasma concentrations of VCR and increased its tissue uptake. It is important to monitor cholesterol and triglyceride levels in ALL patients to avoid aggrevated neurological side effects of VCR and the delay or lack of activity of PSZ.
doi:10.1007/s40268-017-0178-8 pmid:28299646 pmcid:PMC5427049 fatcat:zydbe44tsba6phz6lvan4pman4