Clinical Pharmacology in Women's Health: Current Status and Opportunities

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Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval — An Analysis of ECGs From the IQ-CSRC Study

The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs — moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine — and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (−0.3 and −7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval

Pharmacokinetics, Metabolism, and Excretion of Licogliflozin, a Dual Inhibitor of SGLT1/2, in Rats, Dogs, and Humans

1. The absorption, metabolism, and excretion (AME) of licogliflozin, a sodium-glucose co-transporters (SGLTs) 1 and 2 inhibitor, were studied in male rats, dogs, and healthy male volunteers and reported. 2. Oral absorption of licogliflozin was rapid (tmax < 1 hr) with absorption estimated at 87%, 100% and 77% in rats, dogs and humans, respectively. 3. The excretion of licogliflozin-related radioactivity was rapid and nearly complete following oral administration with total radioactivity recovery ranging from 73% in dogs, 92.5% in humans, to 100% in rats. Dose-related radioactivity was excreted in both urine and faeces with urinary excretion playing a slightly more important role in humans (~56%) than in animal species (~19-41%). 4. The elimination of licogliflozin was predominantly via metabolism with majority of the radioactivity dose (~54-74%) excreted as metabolites across species. 5. The principal biotransformation pathways involved direct glucuronidation and oxidation across all species. In humans, direct glucuronidation to M17 and M27 was the major pathway observed, accounting for ~38% of the dose in excreta while oxidative metabolism also contributed to >29% of the dose in excreta. Oxidative pathways were predominant in animal species

Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects

We describe a mechanistic investigation of drug–drug interaction between aliskiren and grapefruit juice in healthy subjects. Twenty-eight subjects received an oral dose of aliskiren 300 mg (highest recommended clinical dose) with 300 mL water or grapefruit juice concentrate in a two-way crossover design. Safety and pharmacokinetic analyses were performed during each treatment period. Concomitant administration of a single dose of aliskiren with grapefruit juice decreased plasma concentration of aliskiren. The mean decrease in AUCinf, AUClast and Cmax was 38%, 37% and 61%, respectively. Aliskiren administered alone or in combination with grapefruit juice was well tolerated in healthy subjects. To provide mechanistic evidence for the grapefruit juice effect, in vitro transport studies were performed using OATP-subtype transfected HEK293 cells. The uptake of [14C]aliskiren into OATP2B1-expressing cells was essentially the same as that into control cells, and the inhibitor combination, atorvastatin (10 µM) and rifamycin SV (20 µM), had no effect of [14C]aliskiren accumulation in either cell line. The uptake of [14C]aliskiren and [3H]fexofenadine was linear in OATP1A2-expressing cells, and was reduced by naringin (a component of grapefruit juice) with an IC50 of 75.5 ± 11.6 μM and 24.2 ± 2.0 μM, respectively. In conclusion, grapefruit juice decreases exposure of aliskiren via inhibition of intestinal OATP1A2 and it is likely that this effect is not clinically relevant

Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

Sacubitril/valsartan (LCZ696) is an ARNI, which has been approved for the treatment of patients with heart failure. Sacubitril was identified as an inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3 in vitro. “Statins” are OATP substrates and may be co-administered with LCZ696, thus drug interactions might occur. In a clinical study, LCZ696 increases Cmax and AUC of atorvastatin and its metabolites by 2- and 1.3-fold, respectively. In contrast, LCZ696 did not significantly increase systemic exposure of simvastatin and simvastatin acid. To identify the underlying mechanisms for the different LCZ696 statin drug interactions a PBPKmodel was developed. The PBPK model was constructed by incorporating an in vitro Ki value of sacubitril for OATP1B1 and OATP1B3, and a hybrid simvastatin/simvastatin acid model including OATP-mediated Clint,T. This PBPK model depicted simvastatin acid plasma concentration-time profiles and successfully predicted the lack of a DDI effect. An atorvastatin PBPK model was used in combination with the sacubitril model which simulated the DDI effect of sacubitril on atorvastatin. The simulation of portal vein concentrations indicated that Tmax, T1/2 and Cmax of sacubitril and the short atorvastatin Tmax are critical parameters leading to ~1.7-fold Cmax ratio for atorvastatin. Additionally, for OATP substrates with slow absorption, such as simvastatin acid, no drug interaction is anticipated. Similar mechanisms were applied to evaluate the DDI effect for currently widely prescribed statins via OATP inhibition by sacubitril. Finally, parameter sensitivity analyses results predicted maximally no more than 2-fold exposure increase for various statins which are hepatic OATP substrate

Effect of food on the pharmacokinetics of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet in healthy volunteers.

OBJECTIVE: Vildagliptin is an orally active, potent and selective DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha- and beta-cell responsiveness to glucose. RESEARCH DESIGN AND METHODS: This open-label, single-center, randomized, two-period crossover study in healthy subjects (n=23) ages 18-45 years investigated the effect of food on the pharmacokinetics of vildagliptin and metformin following administration of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet. RESULTS: Administration of the fixed-dose combination tablet following a high-fat meal had no effect on vildagliptin AUC(0-infinity) (ratio of geometric mean for fed:fasted state, 1.10 [90% CI 1.03, 1.18]), C(max) (ratio of means 0.98 [90% CI 0.85, 1.13]) or median t(max) (2.5 h in fed and fasted states). The rate of absorption of metformin was decreased when given with food, as reflected by the prolonged t(max) (2-4 h) and reduction in C(max) (by 26%), but the extent of absorption was not changed. The food effect on the metformin component of the fixed-dose combination tablets was consistent with, but of a lesser magnitude compared with data stated. CONCLUSIONS: The vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet can be administered in the same manner as metformin, and can be recommended to be taken with meals to reduce the gastrointestinal symptoms associated with metformin

Effect of food on the oral bioavailability of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide fixed dose combination tablets in healthy subjects

Amlodipine (calcium channel blocker), valsartan (angiotensin receptor blocker) and hydrochlorothiazide (HCTZ, a diuretic) are antihypertensive drugs available as monotherapies. A double fixed dose combination of amlodipine/valsartan and triple fixed dose combination of amlodipine/valsartan/HCTZ tablets have been developed to treat patients with moderate to severe hypertension. In this paper, the effect of food on the oral bioavailability of these two fixed dose combination tablets is presented. Two separate clinical studies were conducted in healthy subjects with each fixed dose combination product using a randomized, open-label, two-period crossover study design with a washout period of at least 14 days. In the study with amlodipine/valsartan combination tablet, a total of 37 healthy male and female subjects received a single 10/160 mg oral dose under fasted or fed conditions. In the study of amlodipine/valsartan/HCTZ tablet, a total of 35 subjects received a single 10/320/25 mg oral dose under fasted or fed conditions. Blood samples were collected at pre-determined time points (predose and up to 168 hours post-dose) in both studies to determine amlodipine, valsartan and/or HCTZ concentrations in plasma simultaneously by a validated LC/MS/MS methods. The PK parameters tmax, Cmax, AUC0-t and AUC0-∞ of these analytes were estimated by non-compartmental analysis. The study results were interpreted based on geometric mean ratios (90% CI) between fed and fasted conditions. Following single dose oral administration of 10/160 mg amlodipine/valsartan fixed combination tablet, amlodipine and valsartan AUCs were comparable between the fed and fasting conditions while the valsartan Cmax was decreased slightly by 14% under fed conditions. The bioavailability of amlodipine, valsartan and HCTZ was similar under fed and fasting conditions following a single dose oral administration of 10/320/25 mg amlodipine/valsartan/HCTZ fixed combination tablet. In conclusion, both fixed dose combination tablets can be administered without regards to meals. Key Words: Amlodipine, valsartan and hydrochlorothiazide (HCTZ), fixed dose combination, food effec

BIOAVAILABILITY OF VALSARTAN LIQUID ORAL DOSAGE FORMS

The oral bioavailability of valsartan from extemporaneous suspension and solution formulation was evaluated relative to tablet formulation in two separate open label, randomize crossover studies in healthy adults. In both studies, plasma concentrations of valsartan after oral administered were analyzed using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and the corresponding pharmacokinetic parameters were estimated using noncompartmental analysis. The peak plasma concentration (Cmax) and area under the concentration time-curves (AUC(0-∞)) of valsartan from the extemporaneous suspension were higher by 1.93- and 1.56-fold, respectively, relative to the tablet formulation (p<0.001). The Cmax and AUC(0-∞) of valsartan from the oral solution were higher by 2.21- and 1.75-fold, respectively, relative to the tablet formulation (p<0.001). These results indicate that both rate and extent of absorption of valsartan are higher from the two liquid dosage forms (extemporaneous suspension and solution formulations) relative to the solid oral dosage form (tablet formulation)