Rising dose tolerance

FIGURE 5.18. Example of rising dose tolerance test [no pharmacokinetic (PK) groups]. 

Hazelette, J., Thompson, T., Mertz, B., Vuolo-Schuessler, L., Gree, J., Tripp, S., Robertson, P. and Triana, V (1987). Rising dose tolerance (RDT) study A novel scenario for obtaining preclinical toxicology/drug metabolism data. Toxicologist 7, Abstract 846. 

Radioactive Drug Research Committee Rising-Dose Tolerance Request for Approval Reduction In Force... 

The diuretic effects, pharmacokinetic effects and safety of CI-977 in 16 healthy human volunteers have been reported over a dose range of 5-25 pg intramuscular injection [9]. CI-977 C ax and AUC(O-oo) values increased in proportion to dose and significant dose-related decreases in negative free water clearance and urine osmolality were observed, in accordance with the diuretic effects previously seen in rodents. Adverse effects include dizziness and fatigue. In another rising, singledose tolerance study in humans doses up to 40 pg were administered intramuscularly. The highest well tolerated dose was 15 pg. No euphoria or dysphoria occurred [10]. 

Local anaesthetics directly depress myocardial conduction and contractility in a dose-dependent manner. They bind to and inactivate myocardial sodium channels, reducing the velocity of the cardiac action potential and prolonging the QRS interval. As plasma concentrations approach toxic values sodium channels become progressively inactivated until there is a generalised reduction in automaticity (cardiac slowing) with negative inotropy. Slow increases to near- or above-toxic levels are better tolerated than rapid rises seen following intravascular injection. 

Despite the relatively stable use pattern Ralph displayed, gently rising tolerance over the years did force him gradually to higher daily doses. The costs and risks associated with his habit had increased over the years, and the need to take larger amounts of drug was one factor heightening those costs. 

Once-daily administration of modified-release formulation of fluvastatin 80-320 mg/day was generally safe and well tolerated in 40 patients with primary hypercholesterolemia over 13 days (7). However, fluvastatin 640 mg in this formulation was not well tolerated six of seven patients had adverse events, including diarrhea, headache, and rises in serum transaminases. In addition, the pharmacokinetics of fluvastatin were non-linear at this dose, possibly because of saturation of first-pass metabolism, causing higher than expected serum drug concentrations. 

Clinical study demonstrated a steady plasma level throughout the day after dosing of a single 60-mg dose with elimination of the rapid rise in plasma concentration seen with IR dosing (20 mg nifedipine administered three times a day) as shown in Figure 22.8. The study also showed that the product was well tolerated with an improved safety proLle. 

Zhang L et al (2011) Pharmacokinetics and tolerability of vandetanib in Chinese patients with solid, malignant tumors an open-label, phase I, rising multiple-dose study. Clin Ther 33 315-327... 

Many biochemistry laboratories no longer undertake routine measurement of the plasma concentration for most anticonvulsant drugs because plasma concentrations are insufficiently stable to serve as a useful guide to change of dose. The exception is phenytoin, where a small increase in dose may lead to a disproportionate rise in the plasma drug concentration (see zero-order pharmacokinetics, p. 99) and plasma monitoring is essential. With other drugs the dose is increased to the maximum tolerated level and, if seizures continue, it is replaced by another. 

When the limits of tolerance are approached, there may be palpitation, extra beats, and a rise in blood pressure. In sensitive individuals or at high doses, ventricular fibrillation, subarachnoid hemorrhage, and even hemiplegia have been known to occur. Adrenahne can occasionally cause pulmonary edema (4,5). It is possible that in at least some of these cases the drug has been inadvertently injected intravenously. 

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