PHARMACOKINETICS OF NIVALIN

Nivalin is rapidly absorbed after subcutaneous injection or oral administration. Therapeutic plasma concentrations are attained within about 30 minutes. Studies of Nivalin pharmacokinetics by Michailova et. al. [11] established no statistically significant differences in the mean AUC values (area under concentration curve) after single subcutaneous and oral dosage in humans. This fact is in favor of using the oral route of administration, unless contraindicated, as the same effect is attained avoiding injection site trauma and associated risks.

Nivalin follows the two-compartment model of distribution, as evident from the characteristic AUC curve, Fig. 4. The apparent volume of distribution in the central compartment is about 4 L. Maximal plasma levels of 1.20 mcg/ml with 10mg single dose are attained within about 2 hours. Plasma half-life is about 5 hours. Elimination from the central compartment is more rapid, compared to elimination from the peripheral compartment. Nivalin has longer half-time of distribution compared to neostigmine and pyridostigmine - 10 min. for Nivalin versus 0.54 - 3.5 min and 5.0-6.6 min. for the latter two drugs. Nivalin half-life is also longer, which shows that it has "mild" but steady action.

Nivalin binds poorly to plasma proteins. It crosses the blood-brain barrier and is distributed in brain tissue.

Fig 4. Distribution of Nivalin in the central compartment (Xc) and in the tissue compartment (Xm) after Michailova, Yamboliev, Zhivkova, Tencheva and Yovovich (Pharmacology, 1989)

Nivalin undergoes slow and minor biotransformation - demethylation of the parent drug to 5-6%. Galanthamine metabolites, epigalanthamine and galanthaminone, are found in plasma and urine.

Nivalin is eliminated chiefly through glomerular filtration. The renal clearance of galanthamine is 1.40 ml/min.kg^-1. It is not conjugated in the liver and its biliary excretion is negligible, 0.2 +/- 0.1% for 24 h.

Unchanged galanthamine and its metabolites (galantaminone, epigalanthamine) are eliminated into the urine at an excretion rate of 89 +/- 20% of the administered subcutaneous dose and 74 +/- 23% of the oral dose for 72 h (Zhivkova, 1989).

The renal clearance of Nivalin is about 100 ml/min and is similar to that of insulin and creatinine. Therefore, when Nivalin is used in patients with impaired kidney function or various degrees of renal failure, it is advisable to adjust its dosage to the creatinine clearance. As extensive studies in that respect are still lacking, in case of chronic renal failure, especially its terminal stage when a so called symptomatic polyneuropathy develops where Nivalin can have beneficial therapeutic effect, the proposed product should be used with caution and the saturation dose should be distributed over a large dosage interval, i.e. between one haemodialysis session and the next, as in the case with aminoglycoside antibiotics.

Nastev et al. [12] recommended 10-15 mg Nivalin as the optimal daily loading dose for long-term treatment in patients with healthy kidneys and normal renal function.