Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers.

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Evaluation of the pharmacokinetic interaction between fluvastatin XL and cyclosporine in renal transplant recipients.

OBJECTIVE: To assess the pharmacokinetic interaction between cyclosporine and extended-release fluvastatin (fluvastatin XL), 80 mg for 7 days, in stable renal transplant recipients. METHODS: This was a single-center, open-label study. 17 renal transplant recipients received their standard cyclosporine therapy (Days 1 - 9) plus a once-daily single oral dose of fluvastatin XL, 80 mg (Days 2 - 8). Blood samples were collected and cyclosporine (whole blood) and fluvastatin (plasma) concentrations determined by radioimmunoassay and HPLC fluorescence detection, respectively. Pharmacokinetic parameters were calculated using non-compartment analysis and fluvastatin results were compared with historical controls. RESULTS: Treatment with fluvastatin XL, 80 mg for 7 days, had no significant effect on either the AUC0-12 (3,644 ng x h/ml in the absence of fluvastatin vs. 3,534 ng x h/ml in the presence of fluvastatin) or the Cmax of cyclosporine (983 ng/ml in the absence of fluvastatin vs. 945 ng/ml in the presence of fluvastatin). Co-administration of fluvastatin XL also had no effect on the tmax, t1/2 or apparent clearance (CL/F) of cyclosporine in renal transplant patients. The AUC and Cmax for fluvastatin XL in the presence of cyclosporine (AUC0-24 1,192 ng. x h/ml, Cmax 271 ng/ml) were approximately 2-fold higher compared with historical data for fluvastatin XL alone in healthy volunteers (AUC0-24 630 ng x h/ml, Cmax 102 ng/ml) but lower than the historical data for fluvastatin IR, 40 mg b.i.d. alone in healthy volunteers (AUC0-24 1,340 ng x h/ml, Cmax 443 ng/ml). Tmax, t1/2 and trough levels of fluvastatin in the presence of cyclosporine were also similar to the historical controls. Concomitant administration of cyclosporine and fluvastatin XL was well tolerated by renal transplant recipients. CONCLUSIONS: Fluvastatin XL, 80 mg, and cyclosporine do not show clinically relevant pharmacokinetic interactions.

Assessment of the bioequivalence of two oxcarbazepine oral suspensions versus a film-coated tablet in healthy subjects.

Oxcarbazepine (trileptal) oral suspension has been reformulated and a study was performed to compare the bioavailability after single doses and at steady state of the current and former oral suspension versus the marketed film-coated tablets and to compare the bioavailability of the current and former oral suspension. The results support the switch from the former oral suspension to the current oral suspension and also from both oral suspensions to the film-coated tablet and vice versa. The study was an open-label, single-center, 3-way crossover trial. Each treatment period consisted of a single dose of 600 mg oxcarbazepine on Day 1, 600 mg oxcarbazepine b.i.d. repeated administration from Day 4 up to including Day 7, and a final dose of 600 mg oxcarbazepine administered on the morning of Day 8. Blood samples were taken on Day 1, Day 7 and Day 8 (pre-dose). Plasma concentrations of the main metabolite of oxcarbazepine (MHD) were determined using a validated HPLC assay. The 2 oral suspensions were compared with the film-coated tablet as reference formulation under fasted conditions. Also the current oral suspension was compared with the former oral suspension. These comparisons were made using data following single dose administration and under steady state conditions. Plasma AUC for single dose and AUC(0-12h) at steady state and plasma Cmax, log-transformed (natural base) were used for the assessment of bioequivalence. The 90% confidence interval (CI) approach was used for testing bioequivalence. Bioequivalence was accepted if CI was contained within the region (0.8, 1.25). At steady state, both the former and the current oral suspensions showed bioequivalence with the film-coated tablet with respect to AUC and Cmax. The current oral suspension was also bioequivalent when compared to the former oral suspension with respect to AUC and Cmax. After single dose, the former oral suspension was bioequivalent when compared to the film-coated tablet with respect to both AUC and Cmax. However, the current oral suspension was bioequivalent to both the film-coated tablet and the former oral suspension with respect to AUC but not to Cmax.

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.

Pharmacokinetics of the conventional and microemulsion formulations of cyclosporine in pancreas-kidney transplant recipients with gastroparesis.

Cyclosporine (CsA) is an immunosuppressive drug requiring dose individualization and regular control due to its highly variable pharmacokinetics. Since gastroparesis may influence the absorption of CsA, a randomized cross-over study was performed to assess the pharmacokinetics and tolerability of a novel microemulsion CsA formulation in comparison with the standard CsA dosage form in six stable pancreas-kidney transplant recipients with scintigraphically proven gastroparesis. The absorption of CsA was investigated during three 2-hr study days during each treatment period, and a full pharmacokinetic profile was done for each formulation. No adverse events or differences in tolerability/safety parameters between the treatments were found. The average AUC (0-->2 hr) was 150% higher after the novel formulation. The coefficient of variation in AUC (0-->2 hr) for both formulations was comparable (37% after the microemulsion and 40% after the standard formulation). The median time at which blood CsA levels exceeded the preceding trough level by 20% was 30 min (range: 30 -> 718 min) after the standard formulation. With approximately the same average dose, the AUCss tau after the microemulsion was 81% higher than the standard formulation, while predose and 12-hr trough levels were similar. The average maximal CsA plasma level after the microemulsion was 396 ng/ml (95% CI: 71-722 ng/ml) higher than after the standard formulation. The median time at which the highest blood levels were observed was 90 min (range: 150 -> 718 min) after the standard formulation. The time profiles of the CsA metabolites followed those of the parent compound. The microemulsion resulted in a higher systemic exposure to CsA than the standard formulation in pancreas-kidney transplant patients with diabetic gastroparesis, but substantial variability in blood concentrations remained.

Multiple-dose pharmacokinetics and distribution in tissue of terbinafine and metabolites.

The pharmacokinetics of terbinafine and its inactive metabolites SDZ 86-621 (the N-demethyl form), SDZ 280-027 (the carboxybutyl form), and SDZ 280-047 (N-demethyl- carboxybutyl form) in plasma were characterized for 10 healthy male subjects receiving 250 mg of terbinafine orally once a day for 4 weeks and in the subsequent 8-week washout phase. Terbinafine concentrations were also measured in sebum, hair, nail, and stratum corneum samples. Concentrations of the parent compound and metabolites were determined by validated high-performance liquid chromatography methods. Terbinafine was rapidly absorbed, with peak concentrations in plasma of 1.70 +/- 0.77 micrograms/ml occurring 1.2 +/- 0.3 h postdose. Concentrations subsequently exhibited a triphasic decline, with a terminal deposition half-life of 16.5 +/- 2.8 days. Terbinafine accumulated approximately twofold over the 4-week dosing phase. The predominant metabolite in plasma samples was SDZ 280-027; specifically, the ratios of metabolite area under the curve to terbinafine area under the curve following the last dose were 1.25, 1.38, and 1.08 for metabolites SDZ 86-621, SDZ 280-027, and SDZ 280-047. Measurable concentrations of terbinafine were achieved in sebum and hair samples within the first week of administration and by week 3 in stratum corneum and nail samples. Fungicidal concentrations persisted in plasma and peripheral tissue samples for prolonged periods (weeks to months) after administration of the last dose. These pharmacokinetic properties are likely an underlying factor in the shorter treatment times and good clinical cure rates which have been reported for terbinafine in the therapy of onychomycoses and dermatomycoses.

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.

Simultaneous determination of terbinafine (Lamisil) and five metabolites in human plasma and urine by high-performance liquid chromatography using on-line solid-phase extraction.

The antimycotic agent terbinafine (Lamisil) and five of its main metabolites were determined simultaneously in human plasma and urine samples by an isocratic HPLC method. The compounds were separated on a phenyl column following on-line solid-phase sample clean-up with a column-switching device. Terbinafine and its metabolites were detected by monitoring the column effluent with UV light at a wavelength of 224 nm. The linear range in plasma was assessed between 0 and 2500 ng/ml for the parent drug and metabolites V, IV and I. The linear response of metabolites III and II was assessed between 0 and 1250 ng/ml. In urine, linearity was assessed between 0 and 10,000 ng/ml for metabolites V, IV, III, II and between 0 and 1000 ng/ml for the parent drug and metabolite I. Quantification limits based on a C.V. < or = 20% and a bias < or = +/- 20% ranged from 20 to 500 ng/ml depending on the compound and the matrix. Inter-day and intra-day variations were similar indicating the ruggedness of the two methods. Due to the considerable differences in hydrophobicity between the compounds, extraction efficiencies ranged from 55 to 100%. Both methods were found to be reproducible and sufficiently sensitive for the evaluation of metabolite pharmacokinetics.

Determination of terbinafine and its desmethyl metabolite in human plasma by high-performance liquid chromatography.

A reliable reversed-phase high-performance liquid chromatographic method has been developed for the determination of terbinafine (Terb) and its desmethyl metabolite (DMT) in human plasma. The analytes and the internal standard (I.S.) are extracted by a liquid-liquid technique followed by an aqueous back-extraction, allowing injection of an aqueous solvent in the HPLC system. The mobile phase is acetonitrile + 0.012 M triethylamine -0.020 M orthophosphoric acid (50:50, v/v) and the UV detection is at 224 nm. The inter-assay precision over the concentration range 2-1000 ng/ml is between 2.9 and 9.8% for both compounds. The limit of quantification, 2 ng/ml for both compounds, is sufficient for investigating the pharmacokinetics of Lamisil in human studies. With an additional preparation step, this method can be used for assaying Terb in tissues such as nail, sebum and stratum corneum.

Levels of terbinafine in plasma, stratum corneum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once per day for four weeks.

The distribution of terbinafine in stratum corneum dermis-epidermis (without stratum corneum), sebum, hair, nails and plasma was studied in human male volunteers during and after 250 mg orally once daily for 28 days. The highest concentration was seen in sebum, 56.07 micrograms/g, after 14 days of therapy. The concentration was still 1.0 microgram/g 44 days after stop of medication. In stratum corneum the highest concentration, 14.4 micrograms/g, was seen 1 day after the last day of therapy, and it was 2.1 micrograms/g 44 days after stop of medication. The concentrations in hair and nails were lower with a maximum of 2.36 and 0.39 micrograms/g respectively, 1 day after stop of therapy, and still 0.21 microgram/g in hair and 0.09 microgram/g in nails 55 days after the last day of medication. With the exception of nails, all other tissue levels were at all times above the plasma concentrations. For nails, tissue levels exceeded that of plasma as early as 1 day after stop of medication, and this difference continued to increase until the last day of tissue sampling, 55 days after the last tablet. These results indicate that terbinafine is delivered to the stratum corneum through sebum and to a minor extent by direct diffusion through dermis-epidermis. Probably short-term therapy with terbinafine may be effective in the treatment of several dermatomycoses, due to the strong binding of terbinafine to stratum corneum for a long time after stop of medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Trials of the bronchodilator activity of the xanthine analogue SDZ MKS 492 in healthy volunteers during a methacholine challenge test.

An approximately steady-state reduction of specific airway conductance was induced in healthy human subjects by means of an individualized inhaled methacholine loading dose followed by a maintenance dose regime. Tested against this background bronchoconstriction, the xanthine analogue SDZ MKS 492, when administered as a single oral dose of 40 mg, showed a significant bronchodilator action, which lasted for up to 5.5 h. Bronchodilatation was not seen after administration of 10 or 20 mg doses. SDZ MKS 492 inhaled as a dry powder had a bronchodilator action that was small, most evident with the 12 mg dose and transient. The peak relief of imposed bronchoconstriction was 29% and the apparent half-time of removal of SDZ MKS 492 from its site of action was 5-6 min. Inhaled SDZ 492 had a bitter taste that was not masked by inclusion of menthol and aspartame in the formulation. The bronchodilatation seen in laboratory animals can also be produced by SDZ MKS 492 in man when administered orally or by inhalation. Its magnitude correlates better with the plasma concentration of parent drug than with that of either of the identified metabolites. Dispositional processes in the lung abbreviate its action after administration by inhalation.

Column liquid chromatographic determination of hydrolysed bopindolol, in the picogram per millilitre range in plasma, using cartridge extraction and dual electrochemical detection.

A highly sensitive and specific column liquid chromatographic assay with electrochemical detection was developed for hydrolysed bopindolol, an active metabolite of bopindolol (Sandonorm) in human plasma. The pre-chromatographic sample preparation involved Extrelut column clean-up followed by liquid extraction of the organic extract into dilute acetic acid. Separation was on a Nucleosil ODS 3-microns column at 40 degrees C, with a phosphate buffer-methanol mobile phase. Detection was performed at +450 mV with an ESA electrochemical detector. Mepindolol was used as internal standard and quantitation was based on peak-area ratios. Total analysis time was 14 min per sample. The recovery rate of the assay was at least 70% for both compounds. A detection limit as low as 25 pg/ml, starting with 1 ml of plasma, was achieved. The day-to-day reproducibility and accuracy, checked with quality-control samples, demonstrated the reliability of this assay used by different analysts, on different chromatographic systems and over a long period of time.

Determination of sub-nanogram amounts of dihydroergotamine in plasma and urine using liquid chromatography and fluorimetric detection with off-line and on-line solid-phase drug enrichment.

A highly sensitive and selective high-performance liquid chromatographic method, involving sample pre-treatment, column switching and fluorimetric detection, is described for the determination of dihydroergotamine in plasma and urine samples. The pre-chromatographic sample treatment consists of extraction by means of an Extrelut column for plasma samples, and pre-separation with enrichment steps on a Sep-Pak column for urine samples. The samples are then injected onto a pre-separation column (Aquapore), and the fraction containing dihydroergotamine are automatically diverted onto an analytical column (ODS reversed phase). An acetonitrile-ammonium carbamate gradient is used as the mobile phase. High recovery of dihydroergotamine from both plasma (87%) and urine (100%) and a detection limit as low as 100 pg/ml were achieved, with a linear response up to 5 ng/ml. The assay demonstrated a high degree of selectivity with regard to the extensive metabolism of dihydroergotamine especially to the main metabolite 8'-hydroxydihydroergotamine. The assay was successfully applied for more than one year to the determination of plasma and urine concentrations of dihydroergotamine after parenteral administration.