Pharmacokinetics of High-Dose Metoclopramide in Cancer Patients

Abstract

The introduction of new cytotoxic drug regimens has been associated with an increase in the incidence and severity of adverse effects. This in turn has highlighted the need for more effective adjuvant therapy. The use of metoclopramide for the prophylaxis of nausea and vomiting, in high intravenous doses (50 to 1000 mg), has become established since 1981. As a lipid-soluble drug, metoclopramide has a large volume of distribution. The reported mean values after high doses range between 2.8 and 4.6 L/kg. The mean values for total body clearance and terminal half-life range from 0.31 to 0.69 L/kg/h and from 4.5 to 8.8 hours, respectively. The values of these pharmacokinetic parameters are essentially similar to those obtained after conventional doses (less than 50mg). Pharmacokinetic parameters appear unaffected by age, although no high-dose study has been conducted in children. Bodyweight is apparently correlated with clearance. An influence of renal function indices on terminal half-life and clearance has been shown, which is rather surprising since renal clearance accounts for only 20% of the total clearance. No thorough investigations exist which examine the influence of hepatic disease, cancer type and cytotoxic drug regimen on the disposition of metoclopramide. A relationship between dose (or concentration) and therapeutic or adverse effects of metoclopramide is outlined. The therapeutic benefit of high doses (up to 14 mg/kg) may be dependent on age, and on the combination of cytotoxic drugs. The advantages of high doses of metoclopramide are most apparent when the drug is used as protection against the adverse effects of high doses of cisplatin (greater than 60 mg/m2). Despite considerable pharmacokinetic variability, intravenous administration of high doses of metoclopramide is relatively safe due to its large therapeutic index.

Population Analysis of the Pharmacokinetic Variability of High-Dose Metoclopramide in Cancer Patients1

“…Why this should be so is less obvious. The most substantial decrease in variance of clearance was actually not achieved " N by introducing demographic factors but by esti- '" (Bryson et al 1985;McGovern et al 1986). The loading and maintenance dose rate of 5000 ~g/min (300 mg/h) and 167 ~g/min (10 mg/h), respectively.…”

“…The text file was transferred to the A 2-compartment pharmacokinetic model was chosen to analyse the concentration-time data because the biexponential decline of concentrations after the maintenance infusion was both visible in the data (referring to individuals in whom 8 to 10 plasma concentrations were measured) and was reported in the literature (Bryson et al 1985). Moreover, both the constant protein binding of metoclopramide over a wide range of concentrations (Webb et al 1986) and a recent review of the pharmacokinetics of high-dose metoclopramide (McGovern et al 1986) support the assumption that a linear pharmacokinetic model is adequate, A recursive solution of a 2-compartment pharmacokinetic model with first-order rate constants is provided in the NONMEM-PREDPP load module with the subroutine ADY AN3. This model updates the amount of drug in the central compartment at every time event after the initial dose.…”

In vitro protection of red blood cell acetylcholinesterase by metoclopramide from inhibition by organophosphates (paraoxon and mipafox)

“…3 µM; MW ≈ 336), but peak plasma concentrations of 3-7.5 µg ml −1 (ca. 9-22.5 µM) can be calculated (Ross-Lee et al, 1981;McGovern et al, 1986). Despite considerable pharmacokinetic variability, MCP is relatively safe owing to its large therapeutic index.…”

A single dose pharmacokinetic study of Gastrobid Continus and Maxolon in the perioperative period.

“…The log of the plasma drug concentration was stable from 2-9 h after administration suggesting that this preparation would be suitable for 8 or 12 hourly administration. However the delay in Cmax may result in delayed or complete absence of clinical effect since a rapid rise in CNS concentration may be important for therapeutic effect (Bateman et al, 1978(Bateman et al, , 1979 McGovern et al, 1983;Taylor & Bateman, 1983;Meyer et al, 1984). Much lower plasma drug concentrations 20 ng ml-' increase gastric emptying after intravenous administration (Bateman et al, 1978).…”

“…Most of the studies relating the plasma concentration of metoclopramide to therapeutic effect have been conducted in patients receiving chemotherapy. These drugs have a profound emetic effect and only very high plasma concentrations of metoclopramide (100-850 ng ml-1) have been reported to be effective (Bateman et al, 1979;McGovern et al, 1983;Taylor & Bateman, 1983;Meyer et al, 1984). Much lower plasma drug concentrations 20 ng ml-' increase gastric emptying after intravenous administration (Bateman et al, 1978).…”