The pharmacokinetics of nedocromil sodium, a new drug for the treatment of reversible obstructive airways disease, in human volunteers and patients with reversible obstructive airways disease.

Abstract

1 The plasma concentrations and urinary excretion of nedocromil sodium have been determined following single dose administration in six healthy volunteers dosed orally (1 mg kg-1) and intravenously (0.2 ,ug kg-1 for 30 min). Similar parameters were measured in six volunteers and twelve asthmatic patients dosed by inhalation (4 mg). Multiple dose kinetic measurements were also made. 2 The intravenous data demonstrated that nedocromil sodium is a high clearance drug (10.2 ± 1.3 ml min-' kg-'). The data were fitted by a two compartment model with very rapid elimination from the central compartment (klo = 0.088 ± 0.021 min-1; ,B = 0.013 + 0.002 min-'). 81% of the dose was excreted in the urine.3 Oral absorption was low (2-3% of the dose) and contributed negligibly to the plasma profile after inhalation. 4 After inhalation of single doses of 4 mg in volunteers and patients plasma concentration rose rapidly, plateaued and then fell monoexponentially with a half-life of approximately 2 h. The data fitted a 'ffip-flop' model with two absorption components. The extent of absorption was up to 6% of the dose with less in patients. 5 After multiple dosing with 4 mg four times daily for 7 days in volunteers negligible accumulation was observed. The pattern was similar in patients treated with 4 mg four times daily after 1, 6 and 12 months.

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

“…Without the availability of IV data (which is frequently not-publicly-available), it is impossible to determine the actual systemic clearance and volume of distribution parameter value (i.e., both can only be determined as apparent parameters, i.e., as a function of the systemic bioavailability). Moreover, drawing conclusions based on inhalation data alone about absorption or dissolution characteristics of the inhaled drug, i.e., the occurrence of the often mentioned flip-flop kinetics after drug inhalation (42,66,92) is not feasible. These identifiability issues are also relevant for orally administered solid dosage forms.…”

The effect of physiological manoeuvres on the absorption of inhaled nedocromil sodium.

“…After inhalation as a nebulised solution, plasma drug concentrations increase rapidly to reach a plateau at 15-20 min, followed by a gradual decline with a half-life longer than that observed after intravenous infusion [1]. Thus the absorption of nedocromil sodium from the bronchial mucosa rate-limits its elimination from the systemic circulation and is dependent on the amount of the drug deposited in the lungs.…”

“…Nedocromil sodium, a pyranoquinoline dicarboxylic acid, used in the treatment of asthma is absorbed exclusively through the lungs when given by inhalation [1,2]. After inhalation as a nebulised solution, plasma drug concentrations increase rapidly to reach a plateau at 15-20 min, followed by a gradual decline with a half-life longer than that observed after intravenous infusion [1].…”

Pharmacokinetics of inhaled drugs

“…In a study of four patients, 40 mg of nebulised are similar to those of sodium cromoglycate in that it exhibits two absorption components consistent with a gentamicin achieved mean levels of 22.2 mg ml−1 in tracheal aspirate and 0.2 mg ml−1 in serum [ 51], 'flip-flop' model [ 45]. As is the case with cromoglycate, the terminal half-life of nedocromil represents the although no details of nebuliser apparatus or sampling times are available.…”

“…After inhalation of 4 mg dose administration, mean peak serum concentration of gentamicin was 1.04 mg ml−1, with levels in bronchial by a pressurised metered dose inhaler, differences were observed between normal volunteers and asthmatic secretions at 4 h (43 mg ml−1) exceeding minimum bacterial inhibitory concentrations. Serum gentamicin patients in terms of a prolonged t max and lower values for C max and AUC in the asthmatics [45 ]. The calculated levels have also been measured 1 h after an 80 mg dose given via a nebuliser, via oral aerosolisation or via a bioavailability for inhaled nedocromil was 9.2% of the nominal dose in normals vs 5.7% in asthmatics.…”