Human pharmacokinetics of dihydroergotamine administered by nasal spray.

OBJECTIVES: A nasal spray of dihydroergotamine was developed for the treatment of migraine headaches, and pharmacokinetic studies were scheduled to evaluate the bioavailability of dihydroergotamine by this new route of administration. METHODS: Nine studies were performed with dihydroergotamine administered by nasal spray to evaluate the bioavailability of the nasal route versus the intramuscular route, the linearity of the kinetics, the interindividual and intraindividual variations, and the influence of different factors. RESULTS: Nasally administered dihydroergotamine (1 mg) becomes rapidly available to the systemic circulation, with peak plasma levels of 1 ng/ml achieved in 0.9 hour. The relative bioavailability versus intramuscular route is 38.4%. Dihydroergotamine administered by the nasal route exhibits linear dose proportionality (1 to 4 mg). Intraindividual variations of bioavailability evaluated for a 1-year period were higher (29%) than those found for the intramuscular route (20%) but comparable to the oral route. Interindividual variations for bioavailability were greater (25% versus 14% by the intramuscular route) but comparable to the oral route. Caffeine contained in the nasal solution (1%) had no effect on the absorption. Vasomotor phenomena, which could also affect the nasal mucosa during a migraine headache, do not modify the bioavailability. The constriction of the nasal mucosa by fenoxazoline leads to a slight decrease (-15%) in the bioavailability. The presence of acute viral rhinitis did not result in any change in dihydroergotamine nasal absorption compared with the normal state of the nasal mucosa. From a pharmacokinetic point of view, nasally administered dihydroergotamine can be given, without risk of overdose, to patients receiving long-term oral dihydroergotamine medication. CONCLUSION: These results show the reliability and reproducibility of this route of dihydroergotamine administration adapted for the treatment of migraine headaches.

In vitro-in vivo correlation of a modified-release oral form of ketotifen: in vitro dissolution rate specification.

The dissolution rate profile of a new modified-release (MR) oral tablet of ketotifen (Zaditen SRO tablet, Sandoz Ltd.) was determined under different conditions (pH, rpm, paddle or basket) with the U.S.P. apparatus. Three different variants of MR tablets were tested. In addition, the in vivo bioavailabilities of these MR tablets were evaluated after a single-dose administration under different conditions (fasting state, with food in morning and/or evening). Several possibilities were evaluated to obtain a correlation between in vitro and in vivo data of the three MR tablets. An excellent linear correlation (r = 0.997) was obtained between the cumulative dissolved percent in vitro and the cumulative absorbed percent in vivo at each time under certain conditions. This was obtained in vitro with the dissolution rate performed in distilled water (37 degrees C) with the U.S.P. apparatus 2 (rotating paddle) and in vivo after a single-dose administration in the morning, fasting state. On the basis of this correlation, of the in vitro dissolution rate for a given variant, and of a simple method of calculation, a reliable prediction of the plasma concentrations obtained following a single dose or at steady state was found. The reliability of this prediction was validated from variants of MR tablet presenting different in vitro dissolution rate profiles and with an upscaled batch which was tested in vivo. This result allows the specifications (upper and lower limits) of the dissolution rate for the MR tablet to be defined and ensures good in vivo characteristics for the different batches of Zaditen SRO tablets during manufacture.

Pharmacokinetics of terbinafine and of its five main metabolites in plasma and urine, following a single oral dose in healthy subjects.

The plasma pharmacokinetics, and the urinary excretion, of terbinafine and its five main metabolites have been investigated after a single oral dose administration of 125 mg to 16 healthy subjects. In plasma, the highest concentrations are observed for the two carboxybutyl metabolites, with a predominance for the carboxybutylterbinafine. For this metabolite, as compared to terbinafine, the Cmax and AUC are 2.4 and 13 times higher respectively. The demethylterbinafine presents a plasma profile close to that of terbinafine. The two hydroxy metabolites are only found as glucuronide and are of minor importance. The apparent terminal half-lives of terbinafine, demethylterbinafine, and the two carboxy metabolites appear to be similar (approximately 25 h). As compared to the plasma concentration of total radioactivity observed after a single oral administration of the same dose of 14C-terbinafine, the parent drug and these five metabolites, account for more than 80% of the total radioactivity in plasma over the 0-48 h interval following administration. In urine, the major metabolite is demethylcarboxybutylterbinafine, which amounted to about 10% of the administered dose. Terbinafine and demethylterbinafine are only excreted as trace amounts in urine. Carboxybutylterbinafine and the two hydroxy metabolites are excreted in the range of 0.5-2% either as glucuronides or free. Urinary excretion over the 0-48 h interval of terbinafine and of the five metabolites amounted to about 14% of the administered dose. This is far below the level of total radioactivity measured in urine over the same interval (approximately 57%), after administration of 14C-terbinafine. This shows in contrast to plasma, that numerous other metabolites are present in urine.

Evaluation of pharmacokinetic studies: is it useful to take into account concentrations below the limit of quantification?

PURPOSE: Based on real data, to evaluate the usefulness of taking into account samples with values below the limit of quantification (LOQ) for the evaluation of pharmacokinetic studies. METHODS: To compare for two drugs, after single dose administration the pharmacokinetic parameters obtained by using a poorly sensitive assay (PSA) and a highly sensitive assay (HSA), acting as reference; To evaluate the results of pharmacokinetic studies in the light of different values for the LOQ. RESULTS: Under certain conditions, such as homogeneous population, sufficient subject number, sufficient sampling times and acceptable accuracy (CV < 20%) for the concentrations, it is possible to get valuable and more reliable kinetic information by using concentrations obtained with a poor precision (CV > 20%). This is especially true for the parameters associated with the terminal phase, such as t1/2 beta and AUC, but also for parameters depending to a lesser extent on the terminal phase, such as t1/2 alpha and AUCm. Moreover, the mean concentration time curve is by far best defined by using all the concentrations. CONCLUSIONS: In some situations, it is preferable to use concentrations with values below the LOQ to evaluate the results of pharmacokinetic studies. However, this should not be the rule, especially when this does not bring any additional information, or when it is possible to increase the sensitivity of the bioanalytical assay.

Pilot study of terbinafine in children suffering from tinea capitis: evaluation of efficacy, safety and pharmacokinetics.

In an open pilot study, 12 children with tinea capitis were treated for 6 weeks with oral terbinafine (125 mg/day), and followed up 2 weeks later. The study was conducted to evaluate the efficacy, safety and pharmacokinetics of terbinafine. All patients were completely cured at the end of the treatment period, and there was no evidence of relapse at follow-up. Seven had a negative culture after 3 weeks of treatment. The time to obtain culture conversion from positive to negative did not appear to be related to body weight, but to clinical severity at baseline. Terbinafine is well tolerated and safe over a 56-day period. The kinetic data show a higher clearance of terbinafine in children compared with adults, with shorter alpha- and beta-phase elimination half-lives. However, a longer terminal gamma-phase (at least 6 days) is observed, as in adults, after multiple dose administration, and this is related to elimination from the tissues. The plasma concentrations are comparable between children and adults at a steady state (125 mg/day).

Pharmacokinetics of terbinafine and five known metabolites in children, after oral administration.

As an extensive study, the pharmacokinetics of terbinafine and five known metabolites have been investigated after single and repeated oral administration to 12 pediatric patients. After single administration of 125 mg terbinafine, four compounds were unconjugated and the hydroxymetabolites appeared in trace amounts as glucuronides. The main metabolites in plasma were unconjugated carboxy compounds. Kinetics of terbinafine and N-desmethylterbinafine metabolite were comparable. The interindividual AUCt variability was similar for terbinafine, N-desmethylterbinafine and carboxyterbinafine. In urine, the major fraction was the hydrophilic unconjugated N-desmethyl-carboxyterbinafine (15%). After repeated administration of 125 mg day(-1), mean trough levels of terbinafine, N-desmethylterbinafine, carboxyterbinafine and N-desmethylhydroxy-terbinafine, and also that of hydroxyterbinafine metabolite were similar, for each compound, on days 21, 42 and 56 denoting that steady state was reached at least on day 21 and no accumulation occurred between days 21 and 56.