Abstract. The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation differences of oral inhaled drug products (OIDPs) that have negligible gastrointestinal bioavailability or for which oral absorption can be prevented (e.g., ingestion of charcoal). PK studies, therefore, may represent the most appropriate methodology for assessing local and systemic bioequivalence (BE). It was believed by many (but not all participants) that potential differences between formulations are more likely to be detected in healthy adult volunteers, as variability is reduced while deposition to peripheral areas is not restricted. A study design allowing assessment and statistical consideration of intra-subject and inter-batch variability within the evaluation of BE studies was suggested, while optimal inhalation technique during PK studies should be enforced to decrease variability. Depending on the drug and in vitro method, in vitro tests may not detect differences in PK parameters. Harmonization of BE testing requirements among different countries should be encouraged to improve global availability of low cost OIDPs and decrease industry burden.
The quantity and consistency of drug delivery from dry powder inhalation devices that incorporate a pre-measured dose in a hard shell capsule of gelatin or other compatible material can be negatively affected by mold release lubricants used in capsule manufacturing. This paper describes a novel process employing supercritical CO2 for selective extraction of the fraction of lubricant responsible for the observed high and inconsistent drug retention in capsules and the ensuing lack of reproducibility of drug delivery. The process allows for lubricant removal from seemingly inaccessible interior surfaces of assembled capsule shells without altering the structural or chemical properties of the capsules. Diffusion limitations are overcome through repeated pressure increase and decrease to generate significant convective flow of dissolved lubricant out of the capsule. Drug retention is alleviated only if nearly all the retentive fraction of the lubricant is removed. The effect of extraction with supercritical CO2 on the structure of the internal surfaces of the capsules is investigated using scanning electron microscopy. Key performance parameters such as drug and carrier retention and fine particle mass are investigated using simulated inhalation tests. Laboratory and pilot scale extractions yielded similar results.
Abstract. In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 μm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 μg tiotropium/ 25 μg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18 μg of tiotropium (Spiriva® HandiHaler®) (TioHH) and 50 μg of salmeterol (Serevent® Diskus®) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, fourway crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss ) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and C max,ss . No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.
In the session on "Pharmacodynamic studies to demonstrate efficacy and safety", presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration-time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of β-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.
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