Safety, Tolerability, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder for Pulmonary Hypertension: A Phase 1, Randomized, Double-Blind, Single- and Multiple-Dose Study.

INTRODUCTION: Treprostinil is a prostacyclin vasodilator widely used for the treatment of pulmonary arterial hypertension (PAH) and, in its inhaled form, for pulmonary hypertension associated with interstitial lung disease (PH-ILD). Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil (TP), an ester prodrug of treprostinil. TPIP is designed to provide sustained release of treprostinil in the lung over a prolonged period, potentially enabling a once-daily (QD) dosing regimen and significantly higher tolerated doses compared with currently available treprostinil formulations. This phase 1 study assessed the safety, tolerability, and pharmacokinetics of TP and treprostinil following single and multiple QD administrations of TPIP in healthy volunteers. METHODS: Healthy adults (aged 18-45 years) were randomized to receive single or multiple QD inhalation doses of TPIP. Participants in the single-dose phase received TPIP 112.5, 225, 450, or 675 µg (n = 6/dose) or placebo (n = 2). Participants in the multiple-dose phase received TPIP 225 µg QD for 7 days (n = 6), 112.5 µg QD for 4 days followed by 225 µg QD for 3 days (n = 6), or placebo for 7 days (n = 4). RESULTS: Overall, 41 of 42 participants (97.6%) completed the study. In the single-dose phase, 70.8% (n = 17/24) of TPIP-treated participants experienced a treatment-emergent adverse event (TEAE) vs 0% (n = 0/2) of placebo-treated participants; the most common TEAEs (≥ 20%) were cough (45.8%), dizziness (29.2%), and throat irritation (20.8%). In the multiple-dose phase, 83.3% (n = 10/12) of TPIP-treated participants experienced a TEAE vs 50.0% of placebo-treated participants (n = 2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), chest discomfort (33.3% vs 0%), and dizziness (25.0% vs 0%). Most TEAEs were mild; only seven patients experienced a moderate TEAE, and no severe or serious TEAEs occurred. In the multiple-dose phase, participants whose doses were titrated from TPIP 112.5 µg QD to 225 µg QD experienced fewer TEAEs than those who received 225 µg QD at treatment initiation (66.7% vs 100.0%), and all TEAEs with dose titration were mild. After a single dose of TPIP, treprostinil elimination t1/2 was 8.67-11.6 h and exposure was dose proportional, with mean (CV%) Cmax 78.4-717 pg/mL (38.6-72.9%) and AUC0-∞ 1090-5480 pg·h/mL (11.5-30.0%). At steady state (TPIP 225 µg), the mean (CV%) of Cmax, Cmin, and AUCτ were 193-228 pg/mL (32.9-46.4%), 17.6-22.8 ng/mL (43.7-64.4%), and 1680-1820 pg·h/mL (28.7-36.6%), respectively. The elimination t1/2 was 6.84-8.82 h after repeat dosing. No steady-state accumulation was observed. Plasma concentrations of TP were below the limit of quantification (100 pg/mL) at all time points measured. CONCLUSION: TPIP was well tolerated at the doses tested, and dose titration improved tolerability. Treprostinil pharmacokinetics were linear and supportive of a QD treatment regimen. These results support further development of TPIP in patients with PAH and PH-ILD.

Differential roles of P-glycoprotein, multidrug resistance-associated protein 2, and CYP3A on saquinavir oral absorption in Sprague-Dawley rats.

The objective of this investigation was to differentiate the roles of P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (Mrp2), and CYP3A on saquinavir (SQV) oral absorption. With use of single-pass jejunal perfusion (in situ) and portal vein-cannulated rats (in vivo), SQV absorption was studied under chemical inhibition of Pgp [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2 isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918)], Mrp2 [(3-(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) ((3-(dimethylamino-3-oxopropyl)thio)methyl)-thio) propanoic acid (MK571)], and/or CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by liquid chromatography-tandem mass spectrometry. When given alone, SQV absorption was extremely low both in situ (F(a) = 0.07%) and in vivo [C(max) = 0.068 microg/ml; area under the curve (AUC) = 6.8 microg x min/ml]. Coadministration of GF120918 boosted SQV absorption by more than 20-fold with decreased variation in AUCs (percent coefficient of variation = 30% versus 100%). In contrast, coadministration of MK571 or midazolam increased SQV absorption only 2- to 3-fold without improving the variation in AUCs. SQV oral absorption was not further improved when it was given with GF120918 and midazolam or with GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that the low oral absorption of SQV is controlled by a secretory transporter, Pgp, and not by limited passive diffusion owing to its poor physicochemical properties. Pgp-mediated transport is also responsible for the highly variable oral bioavailability of SQV. In contrast, intestinal Mrp2 and intestinal CYP3A appear to play minor roles in SQV oral bioavailability. Given the differential and complex roles of Pgp and CYP3A in SQV oral absorption, the optimization of AIDS boosting regimens requires careful consideration to avoid therapy-limiting drug-drug transporter and enzyme interactions.

Estimating human drug oral absorption kinetics from Caco-2 permeability using an absorption-disposition model: model development and evaluation and derivation of analytical solutions for k(a) and F(a).

Intestinal transcellular permeability (P(m)), measured across cell lines such as Caco-2 cells in vitro, is often used for assessing oral drug absorption potential in humans. However, the quantitative link between in vitro permeability and apparent in vivo absorption kinetics, based on drug appearance in plasma, is poorly understood. In the current study, a novel absorption-disposition kinetic model that links traditional pharmacokinetic and mass transfer models was developed. Analytical solutions of k(a) and F(a) were deduced, and using Caco-2 permeability, F(a) in humans was predicted for 51 structurally diverse compounds. Predicted F(a) values were similar to and correlated highly with their corresponding experimental values with an average error of 1.88 +/- 1.06% (-17 to 22%) and r2 = 0.934. Simulated concentration profiles for 17 of 18 drugs corresponded to observed plasma concentration profiles in healthy volunteers. The equilibrium solution for k(a) (k(a,eq)) was found to be a key determinant of F(a), whereas under sink conditions, k(a) is likely to be a determinant of plasma concentration kinetics. The current version of the model offers a quantitative approach for predicting human oral absorption kinetics from in vitro permeability. It also establishes, for the first time, a quantitative link between P(m) and k(a) and between k(a,eq) and F(a). This will facilitate better in vitro or in situ-in vivo correlations since it establishes a basis for incorporating permeability coefficients from the various experimental formats based on drug loss or appearance that are commonly used in the laboratory for permeability determination.

Differentiation of gut and hepatic first pass metabolism and secretion of saquinavir in ported rabbits.

The current study was performed in intestinal and vascular access ported rabbits to quantify and differentiate the components of intestinal and hepatic first pass extraction (i.e., metabolism and secretion) of saquinavir (SQV) mediated by P-glycoprotein (P-gp) and CYP3A. SQV was administered i.v. (1-5 mg/kg) or into the upper small intestine (USI) (5 mg/kg). The roles of intestinal and hepatic secretion by means of P-gp and/or metabolism by CYP3A on the first pass gastrointestinal extraction of SQV were differentiated by using N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (a P-gp inhibitor), midazolam (an inhibitor of CYP3A), or cyclosporine A (an inhibitor of P-gp and CYP3A). The bioavailability (BA) of SQV after USI dosing was 4%. In the presence of CYP3A and P-gp inhibitors, the BA of SQV increased 2- to 11-fold. Based on a relatively unchanged Cmax but prolonged Tmax and t(1/2), P-gp and CYP3A inhibition appeared to alter SQV disposition (i.e., enhanced oral bioavailability by diminishing SQV elimination and by increasing its net intestinal absorption). In conclusion, the current results substantiate the role of the liver and, for the first time, experimentally establish an important role for the intestine in the net absorption and disposition of SQV. The results also demonstrate that changes in SQV disposition due to the modulation of metabolism and secretion were important and may potentially have considerable implications on multiple drug therapeutic regimens used in the treatment of AIDS.

Computation of log BB values for compounds transported through carrier-mediated mechanisms using in vitro permeability data from brain microvessel endothelial cell (BMEC) monolayers.

PURPOSE: To explore the possibility of determining in vivo log BB values (the logarithm value of brain to plasma concentration ratio) from in vitro permeability data measured in brain microvessel endothelial cell (BMEC) monolayers. METHODS: An equilibrium mathematical model was developed: log BB = log(Ca/Cb) + log Kbr:pl, where Cb and Ca are the drug concentrations at equilibrium in the basolateral (B) and apical (A) sides of BMECs in an A-to-B directional diffusion system and Kbr:pl is the brain-plasma partition coefficient. With this model, murine log BB values were calculated for 24 pharmaceutical compounds, mostly Pgp substrates. RESULTS: Calculated log BB values correlated well to experimental values (r2 = 0.854, slope = 0.907 +/- 0.080), demonstrating that the model could reasonably predict brain penetration for compounds that are involved in carrier-mediated transport mechanisms. For a second data set that included volatile organic compounds (log BB = log Kbr:pl), log Kbr:pl values were also shown to correlate well with their respective experimental log BB values (r2 = 0.876, slope = 0.973 +/- 0.082), demonstrating that log Kbr:pl is an excellent descriptor for log BB when a compound penetrates the blood-brain barrier by passive diffusion only. CONCLUSION: The equilibrium model demonstrated a reasonable ability to compute in vivo log BB values, regardless of the involvement or mechanisms of carrier-mediated transport.