TPN171H, a novel phosphodiesterase type 5 (PDE5) inhibitor being investigated for the treatment of pulmonary arterial hypertension (PAH), has successfully concluded a 3-part, phase 1 clinical trial in healthy subjects. The study results were reported in the journal Drug Design, Development and Therapy.
The study found that TPN171H was safe and generally well-tolerated. “Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH,” the authors suggested.
Drug-related adverse events (AEs) were similar to those experienced by patients taking other PDE5 inhibitors, such as sildenafil and tadalafil, and included headache, nausea, nasal congestion, dyspepsia, flushing, nasal congestion, back pain, myalgia, nasopharyngitis, dizziness, and upper respiratory tract infections. In contrast to the other PDE5 inhibitor, sildenafil, TPN171H did not impact color discrimination or blood pressure.
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The authors also noted that the most common drug-related AE was spontaneous erection in male patients and suggested that TPN171H may be a potential treatment candidate for erectile dysfunction in addition to PAH.
PDE5 is the most predominant phosphodiesterase found in the lungs and its activity has been shown to be upregulated in conditions associated with pulmonary hypertension. TPN171H, as in other PDE5 inhibitors, is believed to act through the inhibition of PDE5, which normally cleaves cyclic guanosine monophosphate (cGMP), a second messenger of nitric oxide (NO). PDE5 inhibitors increase NO-mediated vasodilation of the pulmonary artery while exerting anti-proliferative effects on pulmonary artery smooth muscle cells.
The study was divided into 3 parts with the first being a single-ascending-dose trial. Part 2 was a food effect study and the last was a multiple-ascending-dose study. A total of 63 healthy participants were recruited and divided into groups of 28 for part 1, 12 for part 2, and 23 for part 3. In part 1, doses of 5 mg, 10 mg, 20 mg, and 30 mg tablets were administered.
The results showed that the area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) were both linearly related to the dose level. In the food effect portion of the study, it was found that administration of TPN171H in the fed state reduced the peak concentration while also extending the time it took to reach peak concentration compared to the fasted state. In part 3 of the trial, patients were given doses of either 5 mg,10 mg, or a placebo on days 1 and 3-9. Comparison of serum levels showed a slight accumulation of TPN171H upon repeated dosing.
Qian H, Chen Q, Liang L, et al. A phase I study to evaluate the safety, tolerability, and pharmacokinetics of TPN171H, a novel phosphodiesterase type 5 inhibitor, in healthy subjects. Drug Des Devel Ther. 2021;15:2947-2959. doi:10.2147/DDDT.S308610