A series of experiments was conducted to study cyclosporin A (CsA) pharmacokinetics in dogs and the factors influencing variability of blood concentrations. In a first study, influence of feeding on drug absorption and blood profile was evaluated. Administration of CsA as micro-emulsion (ME) formulation with food decreased the bioavailability by 22% and increased the individual variability of drug absorption. In a second study, pharmacokinetic profiles from laboratory fasted beagle dogs receiving orally CsA ME formulation were analyzed. CsA was measured in blood samples by high-performance liquid chromatography (HPLC, 34 profiles) and fluorescent polarization immunoassay (FPIA, 16 profiles). A two-compartment model with first-order absorption was used to calculate the pharmacokinetic parameters. Using FPIA, blood concentrations were 1.5 to 1.7 times higher than when using HPLC, but elimination half-life and MRT were similar. The coefficient of variation of key pharmacokinetic parameters ranged from 27 to 34% following HPLC assay. The same range of variation was obtained after FPIA assay. In a third study, in a clinical trial evaluating CsA for the treatment of canine atopic dermatitis, a single blood sample was collected in dogs which had received CsA for 28 days. No significant correlation was found between clinical improvement and CsA blood concentrations. Considering the large margin of safety of CsA in dogs, the limited inter-individual variability and the lack of correlation between blood concentrations and clinical response, routine monitoring of blood CsA does not appear necessary in dogs with atopic dermatitis.

Relative to healthy subjects, patients with pulmonary arterial hypertension often present with decreased respiratory muscle strength, resulting in decreased maximum inspiratory pressure. Little is known about the impact of reduced respiratory muscle strength on the ability to achieve the peak inspiratory pressures needed for effective drug delivery when using portable dry powder inhalers (≥1.0 kPa). The objective of this study was to assess the impact of inhaler resistance and patient instruction on the inspiratory flow profiles of pulmonary arterial hypertension patients when using breath-actuated dry powder inhalers. The inspiratory flow profiles of 35 patients with pulmonary arterial hypertension were measured with variants of the RS01 dry powder inhaler. Profiles were determined with a custom inspiratory flow profile recorder. Results showed that going from the low resistance RS01 dry powder inhaler to the high resistance AOS® dry powder inhaler led to increases in mean peak inspiratory pressures for pulmonary arterial hypertension subjects from 3.7 kPa to 6.5 kPa. Instructions that ask pulmonary arterial hypertension subjects to inhale with maximal effort until their lungs are full led to a mean peak inspiratory pressures of 6.0 kPa versus 2.1 kPa when the same subjects are asked to inhale comfortably. Significant decreases in mean peak inspiratory pressures are also observed with decreases in lung function, with a mean peak inspiratory pressures of 7.2 kPa for subjects with FEV1 > 60% predicted, versus 3.3 kPa for those subjects with FEV1 < 50% predicted. In conclusion, despite having reduced respiratory muscle strength, subjects with pulmonary arterial hypertension can effectively use a breath-actuated dry powder inhaler. The probability of achieving effective dose delivery may be increased by using dry powder inhalers with increased device resistance, particularly when subjects do not follow the prescribed instructions and inhale comfortably.

Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration ''as needed'', to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH). Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs). Results: RT234 was generally safe and well tolerated at single doses of 0.2-2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The t max occurred at the time that the first blood sample following completion of dosing. After C max was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra Ò ) than after administration of any dose level of RT234. During repeated dose administration of RT234, C max was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t 1/2 values were comparable after single-and repeated-dose administration. Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.

RT234 is an inhaled formulation of the phosphodiesterase type-5 inhibitor (PDE5i) vardenafil, and is being developed for 'as-needed' use for episodic symptoms of pulmonary arterial hypertension (PAH). This study assessed the hemodynamic (HD) response to RT234. METHODS: A multicentre, open label, Phase 2a escalating dose ongoing clinical trial to evaluate acute changes in pulmonary vascular resistance (PVR) and other HD parameters in PAH patients on stable maintenance dual therapy. Three cohorts of 5 subjects each were to receive 0.2, 0.6, 1.2 mg RT234 during right heart catheterization. HD parameters were recorded at 5, 15, 30, 45, and 60-min post-inhalation. RESULTS: Of the 14 subjects enrolled, mean age was 54AE14 years (79% females). 57% of subjects were functional class (FC) II, 36% FC III, and 7% FC IV. All subjects took a long-term oral endothelin receptor antagonist combined with oral PDE5i. Mean baseline PVR was 635AE344, 469AE431, 579AE337 dyn/sec/cm-5 for the 0.2 mg, 0.6 mg and 1.2 mg cohorts respectively. RT234 administration at 0.2 mg, 0.6 mg and 1.2 mg dosages reduced PVR by-6.6% (-22.2 to 2.7),-23.7% (-44.7 to-18.6), and-16.0% (-22.7 to-10.5), respectively. With the 0.6 and 1.2 mg doses, PVR fell by >10% at 5 min, and the reduced PVR was sustained at least 60 mins. PVR/SVR ratio changed by-8.0% (-27.1 to 14.1),-18.4% (-37.8 to 0.9) and-11.9% (-23.9 to-0.3) for the 0.2, 0.6 and 1.2 mg doses respectively, indicating that the 0.6 mg dose may offer the greatest pulmonary selectivity. No clinically significant changes in systemic blood pressure or heart rate were observed. The change in PaO2 was þ1.8% (-13.5 to 27.4), þ8.1% (-13.5 to 22.6) and þ4.3% (-1.4 to 9.9) for the three dose levels. Improvements in pulmonary HD with 0.6mg inhaled RT234 were on par with 20mg oral vardenafil, but with less systemic hypotension and higher oxygenation. The only treatment related adverse events (AE) observed were a mild headache and mild throat irritation, each in a single subject. No respiratory AEs (cough, dyspnoea, wheezing, bronchospasm) occurred. CONCLUSIONS: RT234 inhalation resulted in rapid reduction in PVR that was sustained for at least 60 min post-administration and was well tolerated. The optimally effective dose of RT234 appears to be 0.6 mg. RT234 is well-suited for further clinical development as an "as-needed" or even pre-emptive therapy in PAH. CLINICAL IMPLICATIONS: The observed acute improvements in HD should enable PAH patients to perform more of their activities of daily living, resulting in an improved quality of life.

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