clinical pharmacokinetics of pradigastat, a novel ...highest clinical dose) to that of the 30 mg iv...

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Cite this article: Chen J, Meyers D, Keefe D, Yu J, Sunkara G (2017) Clinical Pharmacokinetics of Pradigastat, a Novel Diacylglycerol Acyltransferase 1 Inhibi-tor. J Drug Des Res 4(3): 1044.

*Corresponding authorJin Chen, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA, Tel: 1 862-778-1630; Email: jin.

Submitted: 01 March 2017

Accepted: 11 April 2017

Published: 12 April 2017

ISSN: 2379-089X

Copyright© 2017 Chen et al.

OPEN ACCESS

Keywords•Pradigastat•LCQ908•Pharmacokinetics•Pharmacodynamics•Familial chylomicronemia•FCS•ADME

Review Article

Clinical Pharmacokinetics of Pradigastat, a Novel Diacylglycerol Acyltransferase 1 InhibitorJin Chen1*, Dan Meyers1, Deborah Keefe2, Jing Yu3 and Gangadhar Sunkara1

1Novartis Institutes for BioMedical Research, East Hanover, USA2Novartis Pharmaceuticals Corporation, East Hanover, USA3Novartis Institutes for BioMedical Research, Cambridge, USA

Abstract

Familial chylomicronemia syndrome (FCS) is a rare lipid disease resulting in severe hypertriglyceridemia caused by complete lipoprotein lipase (LPL) deficiency. Pradigastat, a highly potent and specific diacylglycerol acyltransferase 1 (DGAT1) inhibitor that blocks chylomicron triglyceride (TG) synthesis, is an attractive therapy for patients with FCS.

Objective: To summarize the data from in vitro and clinical pharmacokinetic studies of pradigastat

Results: Following oral administration, pradigastat was slowly absorbed and slowly eliminated. Food intake did not impact pradigastat exposure to any clinically relevant extent. Pradigastat was primarily metabolized by hepatic glucuronosyl transferase (UGT) enzymes UGT1A1 and UGT1A3, and elimination occurred via faeces through the biliary pathway. In patients with severe hepatic impairment, pradigastat exposure was doubled; but not in patients with mild to moderate hepatic impairment or with renal impairment. Pradigastat displayed low drug-drug interaction potential, exhibiting no interaction with atazanavir, probenecid, rosuvastatin, digoxin, warfarin, or oral contraceptives. In FCS patients, pradigastat substantially reduced plasma fasting TG levels (70% at 40 mg), post-prandial TG, and apolipoprotein B-48. Pradigastat had no effect on the QTc interval in humans, hence there was no risk of pro arrhythmia typically associated with prolonged QTc; and, pradigastat also did not induce photosensitivity in humans at the highest clinical dose of 40 mg.

Conclusion: Pradigastat could be taken without food. No dose adjustment was needed in consideration of its drug-drug interaction potential, and no dose adjustment was needed for patients with mild to moderate hepatic impairment or with renal impairment.

ABBREVIATIONSADME: Absorption Distribution Metabolism Excretion;

DGAT1: Diacylglycerol Acyltransferase 1; FCS: Familial Chylomicronemia Syndrome; TG: Triglyceride

INTRODUCTIONMetabolic diseases, such as familial chylomicronemia

syndrome (FCS), are often characterized by excessive triglyceride (TG) accumulation in the liver, plasma, or adipose tissues [1-6]. FCS is a rare autosomal recessive genetic disorder caused by a complete deficiency in lipoprotein lipase (LPL) activity due to mutations in the LPL gene, or genes encoding proteins or enzymes

directly affecting LPL activity [7-9]. FCS is characterized by severe hypertriglyceridemia, pathological persistence of plasma chylomicrons in both fasting and post-prandial conditions, and at least one clinical feature of chylomicronemia, such as eruptive xanthomas, lipemia retinalis, recurrent abdominal pain, hepatosplenomegaly, and, most notably, an increased risk of severe and life-threatening pancreatitis [7]. In patients with FCS, this risk is increased by more than 300-fold [10]. Although reducing TG levels decreases the risk of pancreatitis in patients with chylomicronemia, current TG-lowering drugs and hypertriglyceridemia treatments have little or no effect in patients with FCS, or are restricted only to patients with severe FCS [7,11]. Furthermore, the current standard of care in FCS


Chen et al. (2017)Email:

J Drug Des Res 4(3): 1044 (2017) 2/10

focuses on the implementation of a very low-fat diet [7,12], which is a lifestyle modification that is often difficult to adhere to and maintain long-term.

Pradigastat is a potent and selective inhibitor of diacylglycerol acyltransferase1 (DGAT1), studied by Novartis primarily for the treatment of FCS. DGAT1, a microsomal enzyme catalyzing the final step of TG synthesis, is localized in the endoplasmic reticulum and is highly expressed in the small intestine and adipose tissue [7,8]. Pradigastat has been shown to decrease body weight and post-prandial and fasting TGs, and it could improve glucose profiles [6,13]. Furthermore, a single oral dose of 300 mg pradigastat is generally well-tolerated with no safety concerns reported in healthy subjects [13]. However, transient gastrointestinal (GI) adverse events have been observed following pradigastat treatment [6]; similar events have also been reported with other DGAT1 inhibitors [14].

Pradigastat has been evaluated in a number of clinical trials involving healthy volunteers, and involving patients with FCS and other metabolic conditions. As such, the aim of this paper is to provide a comprehensive review on the clinical pharmacokinetics of pradigastat.

Pharmaceutical properties of pradigastatPradigastat (trans-4-[4-[5-[[6-(trifluoromethyl)-3-pyridinyl]

amino]-2-pyridinyl]phenyl]cyclohexane acetic acid) is a potent, small-molecule DGAT1 inhibitor with a molecular weight of 455.5 Da (Figure 1) [15,16]. Pradigastat has a very low solubility in water (2.3 mg/mL) and the pH ranges between 1 and 7 (< 13 µg/mL) [17]. Permeability using Caco-2 cells was considered moderate-to-high [17]. Due to low solubility and moderate-to-high permeability, pradigastat has been classified as a biopharmaceutical classification system (BCS) class II compound [17].

Bioanalytical methodsIn clinical studies, pradigastat concentration in human

plasma and urine has been quantified through a validated liquid chromatography-tandem mass spectrometric (LC–MS/MS) method [6,13,17-21] using stable isotope labelled pradigastat (13C2C23

2H4H20F3N3O2) as the internal standard [15]. Samples were extracted by protein precipitation using acetonitrile, followed by dilution with 0.1% formic acid in an acetonitrile: water mixture (50:50; v/v) and were injected into the LC–MS/MS system. Chromatographic separation was performed on a C18 column using an isocratic flow of 0.1% formic acid in water and 0.1% formic acid in acetonitrile or methanol at a flow rate of 0.1-0.4 mL/min. A tandem mass spectrometer equipped with an electrospray ionization interphase was used as the detector, which was scanned in selected reaction monitoring mode with the precursor/product ion combination of m/z 456/316 (pradigastat) and m/z 462/316 (internal standard). The lower limit of quantification (LLOQ) was 1.0 ng/mL and the linear calibration was generally in the range of 1 to 4000 ng/mL and 1 to 1000 ng/mL for plasma [17] and urine [18] samples, respectively.

Pharmacokinetic properties of pradigastatAbsorption and bioavailability: In the first-in-human

study, pradigastat was administered as single (1, 3, 10, 30, 100 or 300 mg) or multiple (1, 5, 10, or 25 mg once daily for 14 days) ascending oral doses in healthy subjects [13]. Following a single

oral dose, the mean concentration-time curve showed an initial peak at approximately 4 hr, and a second and maximum peak at Tmax of ~10 hrpost-dose, suggesting the absorption process may involve enterohepatic recirculation or distal GI tract absorption of pradigastat [13]. Consequently, large inter-subject variability in pradigastat pharmacokinetics was observed, with coefficients of variation (CV%) ranging from 44% -81% for the peak plasma drug levels (Cmax) and 32% –85% for area under the curve (AUC0-

24), respectively [13]. The less-than dose-proportional increase in exposure across the 1 -300 mg dose range indicated that the extent of absorption was likely limited by the poor solubility of pradigastat at higher doses [13]. After 14 days of daily dosing, a steady-state was reached with a 10- to 17.6-fold accumulation, consistent with the frequency of once-daily dosing and its long elimination half-life.

In an intravenous (IV) dose-escalation study, a dose-dependent increase in exposure was observed with the 10, 30, 100 and 115 mg doses; the terminal elimination phase of the plasma concentration-time curves were parallel and similar, indicating no change in the elimination rates across this dose range [22]. The mean terminal half-life of pradigastat was similar to that observed with oral dosing; the clearance (CL) was 0.3-0.5 L/hr with volume of distribution at steady state(Vss) of 30.9-75.8 L. The associated variability in exposure was lower (15-46%) than for oral administration.

The absolute oral bioavailability was calculated to be ~41% by comparing the exposures from the 40 mg oral dose (the highest clinical dose) to that of the 30 mg IV dose. The single dose pharmacokinetic parameters are summarized in (Table 1).

Effect of food intake: The effect of food intake on the pharmacokinetics of pradigastat in healthy adult subjects was evaluated in two open-label, randomized, parallel, studies [17]. A parallel design was applied due to the long half-life of pradigastat, which would otherwise impact the feasibility of a cross-over design.

In one study, the effect of an FDA standard high-fat meal (800-1000 kcal, 50% fat by calories) on the pharmacokinetic exposure of pradigastat was evaluated relative to that under fasting state at a single 20 mg dose in 2 cohorts of 48 subjects (n = 24/cohort) receiving pradigastat with or without food [17]. The Cmax and AUC increased by ~40% in the presence of a high-fat meal. In the second study, in addition to the high-fat (FDA standard) meal, the effects of a low-fat meal (800-1000 kcal, 15% fat by calories), typically recommended for patients with FCS, were also investigated at the highest oral clinical dose of 40 mg in 3 cohorts of 72 healthy subjects (n = 24/cohort). In this study, Cmax increased by 8% and 20% with the low- and high-fat diets, respectively, and AUC increased by 18% with either the low-fat

Figure 1 Chemical structure of pradigastat.



J Drug Des Res 4(3): 1044 (2017) 3/10

Table 1: Summary of single dose pharmacokinetic parameters of pradigastat in clinical studies.

Study Population Subjects(n)

Pradig-astat dose

(mg)

Fed or fasted state

Tmax(h)

T½(h)

Cmax(ng/mL)

AUClast(h.ng/mL)

AUCinf(h.ng/mL)

CL/F(L/h)

Vz/F(L)

First-in-human:Meyers (2015)

[13]

Overweight or obese 7

1188108

131030100300

Fasted8 (2-12)8 (2-72)10 (4-12)10 (4-24)11 (3-120)10 (2-48)

NC58.4 (20.6)67.5 (21.2)100 (43.3)68.4 (25.7)80.2 (29)

23.5 (50)66.0 (81.3)124 (44.4)303 (49)693 (54.5)1,065 (78.7)

365 (98.5)3,112 (94.5)5,173 (26.2)20,413 (44.9)59,468 (48.2)93,575 (74.6)

228 (49.9)*821 (39.3)*1,941 (32.1)*4,995 (50.5)*12,203 (63.9)*18,561 (85.7)*

Human ADME:Upthagrove (2014) [23]

Healthy male subjects

4 10 - 15 143 105 - 21,200 0.5 102.6

Food Effect: Ayalasomayajula

(2015)[17]

Healthy subjects24

22

24

23

18

20

20

40

40

40

Fasted

High-fat meal

Fasted

Low-fat meal

High-fat meal

17 (4-120)

12 (4-48)

10 (4-72)

10 (6-48)

12 (4-96)

153 (59.2)

139 (34.4)

161 (132)

219 (190)

255 (158)

246 (92.2)

304 (192)

22,100 (14,527)

29,730 (16,759)

19,700 (11,600)

22,600 (11,600)

25,000 (18,400)

23,130 (15,520)

30,270 (16,873)

- -

Hepatic Impairment:

Hirano (2015) [19]

Patients with hepatic impairment:

MildModerate

SevereHealthy subjects

10106

26

20 Fasted36

(4–96)7 (2–72)24

(1–96)48 (4–144)

154 (57.9)

131 (28.2)

109 (24.1)

133 (45.0)

95.1 (82.0)

145 (72.5)

180 (99.2)

102 (94.4)

18,900 (15,200)21,600

(13,400)23,700

(11,800)14,800 (8,370)

21,800 (16,100)22,900

(14,700)24,400

(12,200)15,600 (8,810)

1.23 (0.576)

1.37 (1.16)1.13

(0.854)1.67

(0.821)

272 (154)247

(213)161

(80.0)305

(153)

Renal Impairment:Mita (2015) [18]

Patients with renal

impairment:

MildModerate

SevereHealthy subjects

9109

28

40 Fasted10

(4–48)36 (4–120)

12 (2–48)24 (4–120)

154 (53.2)

134 (38.3)

139 (34.4)

138 (44.1)

182 (202)237

(169)287

(99.0)212

(131)

24,900 (19,200)50,500

(56,400)40,700

(25,500)35,000

(24,800)

26,600 (20,300)54,300

(63,300)42,200

(26,700)37,100

(28,100)

2.40 (1.66)1.40

(0.870)1.22

(0.547)1.54

(1.02)

523 (386)250

(164)248

(145)292

(230)Data presented as means (SD) except Meyers et al. 2015[13] which is presented as means (%CV). Tmax presented as median (range). CV: co-efficient of variation; NC: not calculated; *AUC0-24h



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Table 2: Effect of food on pharmacokinetics of pradigastat.

Trial Dose (mg) Test N fed,N fasted PK parameter Geo-mean ratio Lower 90% CI Upper 90% CI

Study1[17] 20 High-fat meal 22, 24Cmax 1.38 1.05 1.83

AUC0-168 1.42 1.07 1.87

Study 2[17] 40Low-fat meal 23, 24

Cmax 1.08 0.84 1.39AUC0-168 1.18 0.93 1.50

High-fat meal 18, 24Cmax 1.20 0.92 1.58

AUC0-168 1.18 0.91 1.53N: number; PK: pharmacokinetic; CI: confidence interval; Cmax: maximum serum concentration that a drug achieves; AUC: area under the curve

A)

B)

Figure 2 (A) Effect of co-administered drug pharmacokinetics. Cmax: maximum measured concentration of drug in plasma; CI: confidence interval; AUC: area under curve; LVG/EE: levonorgestrel-ethinylestradiol; AUCtau: area under the concentration-time curve over uniform dosing interval tau; AUCinf: area under the concentration-time curve extrapolated to time infinity.

or high-fat meal (Table 2). In summary, the positive food effect results (~20-40%) were as expected for a BCS class II compound; however, they were not considered clinically relevant.

Distribution and protein binding: Following IV administration of 10-115 mg pradigastat, the mean volume of distribution was greater than total body water, indicating extravascular and tissue distribution [22]. In vitro investigations demonstrated that pradigastat was mainly distributed into plasma and was extensively bound (> 99%) to plasma protein.

Both distribution and protein binding were concentration independent. Further investigation indicated that pradigastat was highly bound to human serum albumin (> 98%) in the concentration range of 0.05-10 µg /mL, which was inclusive of the therapeutic plasma concentration range [19].

Metabolism: Metabolic clearance of pradigastat occurred primarily via direct glucuronidation, with minimal involvement of oxidative metabolism [23]. The hepatic glucuronosyltransferase



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(UGT) enzymes, UGT1A1, UGT1A3, and UGT2B7, were identified as the main enzymes involved in pradigastat metabolism pathway. UGT1A1 and UGT1A3 were determined to be responsible for 44% and 39% of the glucuronidation of pradigastat in human liver microsomes, respectively, whereas UGT2B7 contributed 17% to the overall activity [23].

The in vivo metabolism and excretion of pradigastat was investigated in a mass balance study following a single oral dose of 10 mg [14C]-pradigastat [23]. The radioactivity in plasma consisted predominantly of unchanged drug with both glucuronide metabolites and a monohydroxy metabolite detected only in trace amounts. The highest metabolite concentration measured was approximately 5% of the total pradigastat concentration in plasma. Due to the instability of glucuronide metabolites in the gut, which are susceptible to hydrolysis to the parent compound, the extent of pradigastat clearance attributable to the glucuronidation pathway was difficult to estimate accurately.

Elimination: In the human mass balance study, excreted radioactivity was almost completely recovered (mean ± SD; 91.5 ± 12.3%) within 28 days after dosing with [14C]-pradigastat [23], with a measured mean elimination half-life of 143 hr and a mean systemic clearance (CL/F) of 0.5 L/hr. Effectively all of the [14C]-pradigastat dose was recovered in the feces, with negligible renal excretion (0.38% of the dose) [23]. Recovered radioactivity was predominantly parent pradigastat, with the hydroxy metabolite constituting only a negligible fraction and the glucuronide metabolite not detected in excreta. In other studies, the concentrations of pradigastat measured in urine samples from healthy subjects, and patients with hepatic impairment and renal impairment were all extremely low, negligible, or undetectable [18,19]. Therefore, elimination of pradigastat in humans occurs via fecal excretion through biliary pathways either as a glucuronide conjugate or unchanged drug.

Accumulation and steady-state pharmacokinetics: Due to the long half-life, steady-state level is approximately reached after 14 days of once-daily oral administration [13]. In clinical drug-drug interaction (DDI) studies, to achieve steady-state plasma levels of pradigastat faster, 3 days of a once-daily 100 mg dose was administered followed by a once-daily 40 mg dose. With this loading dose regimen, steady-state has been achieved as early as Day 4 [17,20,21,24-26]. The steady-state pharmacokinetic parameters are summarized in (Table 3).

Pharmacokinetics of pradigastat in sub-populations: The influence of gender, age and body weight on the pharmacokinetics of pradigastat were evaluated via across study comparison and also by using population PK analysis through a nonlinear mixed effects modeling (data on file, Novartis Pharmaceuticals). The population PK analysis included 904 male and 380 female, 739 healthy and 545 patients (439 T2DM, 72 non-FCS, 34 FCS), aged between 18 and 77 years, with a weight ranging from 36.5 to 153.7 kg. Statistically significant covariates were identified during the stepwise covariate model development and also confirmed by the covariate effect odds ratio of 1 and the 95% confidence interval from the bootstrap result; however, only those with the 95% confidence interval fall ouside of the 80-125% range are considered as having clinical significance.

Gender: Subjects who participated in the clinical studies described in this review were predominantly male [6,13,17,19-21,24]. The first-in-human study where only a few female subjects were recruited reported similar pharmacokinetics for both male and female subjects [13]. Additionally, in a study evaluating the pharmacokinetic interactions of pradigastat and a combination oral contraceptive in 24 healthy female subjects [25], steady-state pradigastat exposures were comparable with other DDI studies comprising both male and female subjects. Population pharmacokinetic analysis confirmed females have only 22% (95% CI: 15-28%) lower weight-adjusted clearance compared to male subjects, which was considered mild and not clinically significant.

Age: Subjects included in the studies reported herein have generally been ≤ 65 years of age [6,13,17,19-21,24]. No studies have been conducted in adolescents or children. Population pharmacokinetic analysis, which included 1284 subjects aged 18-77 years (126 aged ≥ 65 years and 6 aged ≥ 75 years), found that age does not have an effect on oral clearance or steady-state pradigastat (Supplemental Figure 1).

Body weight: Overall, body weight does not have a significant effect on the pharmacokinetics of pradigastat. Population pharmacokinetic analysis confirmed only a small increase (12%) in clearance (95% CI: 6-18%) and 8% increase in central volume of distribution (95% CI: 1-15%) when body weight increased from 75 kg to 94 kg (25th and 75th percentile of the overall population, respectively), which would not result in a clinically meaningful change in steady-state exposure.

Ethnicity: The majority of clinical study participants have been Caucasian [6,13,17,19-21,24] with several studies also reporting a high proportion of patients with Hispanic/Latino ethnicity [17,24]. A study similar in design to the single oral dose ascending part of the first-in-human study (Part I, described in section 4.1) [13] was conducted in healthy Japanese subjects and showed mean Cmax and AUC comparable to those of Caucasian subjects observed in the first-in-human study [13] receiving equivalent doses (Supplemental Figure 2). In Japanese subjects, the median Tmax was 10 hr, T½ ranged from 105 to 156 hr (data on file, Novartis Pharmaceuticals), and like the first-in-human study reported by Meyers et al. [13], exposure increased in a less than dose-proportional manner over the dose range evaluated. Using the population pharmacokinetics analysis, Asian ethnicity was associated with a 23% (95% CI: 13-30%) reduction in clearance and with a 46% (95% CI: 14-81%) increased rate of pradigastat absorption. While statistically significant to the model, these effects did not lead to a clinically meaningful increase in pradigastat exposure.

Healthy subjects and patients: Pradigastat clinical pharmacokinetic studies have largely been performed in healthy volunteers and the findings are described in the preceding sections of this review. Pradigastat has also been evaluated in specific patient populations, including patients with hypertriglyceridemia due to complete deficiency of LPL (FCS), patients with hypertriglyceridemia due to partial deficiency of LPL (non-FCS), patients with type 2 diabetes mellitus (T2DM) and hepatitis C viral infected (HCV) patients. A cross-study comparison of pre-dose exposure for the 20 mg dose level at



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steady-state did not reveal any significant differences among healthy subjects and patient populations (Supplemental Figure 3).

In an open-label, three-period, sequential treatment study where six patients with FCS who were maintained on a low-fat (~20%) diet received 2 weeks of treatment with once-daily doses of 40, 20 or 10 mg pradigastat [6], there was a dose-proportionate increase in pradigastat exposure. Despite high variability and small sample size, in general steady-state exposures of pradigastat were comparable between FCS patients and healthy subjects (Table 3).

Hepatic impairment: Pradigastat is predominantly eliminated via fecal excretion through the biliary route. In an open-label parallel-group study the pharmacokinetics of pradigastat was evaluated in patients with mild (class A, Child-Pugh score 5-6), moderate (Class B, Child-Pugh score 7-9), and severe (class C, Child-Pugh score 10-15) hepatic impairment; matched pair-wise (by gender, race, age and weight) with healthy subjects (Child-Pugh score < 5) after a single oral dose of 20 mg [19]. Overall, as compared to their respective matched healthy groups, the exposures (Cmax and AUC) were similar in patients with mild and moderate hepatic impairment (Table 1). However, systemic exposure doubled (2- and 2.7-fold increases in AUCinf and Cmax, respectively) and Vz/F and CL decreased by approximately half in patients with severe hepatic impairment [19]. The elimination half-life of pradigastat was comparable amongst all of the patients in the study and there was no clear association between pradigastat exposure (AUCinf or Cmax) and albumin or bilirubin levels [19]. Furthermore, plasma protein binding was unaffected by hepatic dysfunction. Based on this result, dose adjustments would not be considered necessary in the patients with mild and moderate hepatic impairment.

Renal impairment: Even though elimination of pradigastat through the renal route is minimal, there has been substantial clinical evidence indicating that renal impairment could also affect the metabolism and transport of drugs that are cleared through non-renal routes, such as hepatic/biliary pathways [27]. Moreover, impaired renal function has been shown to alter hepatic clearance, absorption, plasma protein binding, transport and distribution of drugs [27-29]. Consequently, the effect of impaired renal function on pradigastat pharmacokinetics was assessed in an open-label, 40 mg single-dose study in patients with varying degrees of renal impairment (as defined by the estimated creatinine clearance [CLcr], mild: CLcr 50-80 mL/min, moderate: CLcr 30-50 mL/min and severe: CLcr < 30 mL/min and matched healthy subjects: CLcr > 80 mL/min) [18]. The pharmacokinetics (Cmax and AUCinf) of pradigastat in patients with mild and moderate renal impairment remained mostly unchanged while in the severe renal impairment group the mean exposure Cmax and AUCinf increased by 40 and 18%, respectively, compared with healthy subjects (Table 1). However, this level of change was not considered clinically relevant, as pradigastat efficacy and safety profiles were not adversely affected by this level of increased drug exposure. In line with other studies, pradigastat urinary elimination was minimal (< 0.01% of the dose) and plasma protein binding was unaffected by renal function. Overall, no significant correlation was observed between renal function (CLcr) and Cmax or AUCinf.

Drug interactions: Several clinical studies have been

conducted to investigate the potential interactions between pradigastat and commonly administered co-medications, based on in vitro drug interaction assessment (Table 4). The effect of UGT inhibitors on pradigastat pharmacokinetics was evaluated for probenecid (a general UGT inhibitor) [30] and atazanavir (a UGT1A1/1A3 inhibitor) [30]. Drugs that may be impacted by co-administration with pradigastat included rosuvastatin (a BCRP, OATP substrate) [21], digoxin (which has a narrow therapeutic index), warfarin (which has a narrow therapeutic index) [24], oral contraceptives (a common co-medication) [25], repaglinide (a CYP2C8 substrate), efavirenz (a CYP2B6 substrate) [26] and acetaminophen (a biomarker for delayed gastric emptying effect) [20]. In most studies the pharmacokinetics of both co-medications and pradigastat were measured. The study design and summary results can be found in (Table 4).

In vitro drug-drug interaction assessment: Data from in vitro studies have shown that pradigastat was metabolized by UGT1A1, UGT1A3, and UGT2B7, and it was not a substrate for multidrug resistance protein 2 (MRP2), P-glycoprotein (P-gp), organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or 2B1 (OATP2B1). In vitro, pradigastat did not inhibit transporters, such as MRP2, sodium-taurocholate co-transporting polypeptide (NTCP) or P-gp (IC50 ≤ 50 µM) [21].

Pradigastat, however, inhibited the transporter activities of the breast cancer resistance protein (BCRP; IC50 5 µM), organic anion transporting polypeptides, OATP1B1 (IC50 1.66 μM), OATP1B3 (IC50 3.34 μM), OATP2B1 (IC50 1.34 μM), and organic anion transporter-3 (OAT3; IC50 0.97 µM) in a dose-dependent manner, which suggested potential for DDIs between pradigastat and substrates of these transporters [21].

Pradigastat showed weak inhibitory potency for cytochrome P450, CYP2B6 and CYP2C8 with estimated Ki (IC50/2) values of 8.5 and 6.4 µM, respectively. Pradigastat did not effectively inhibit other key CYP isozymes [24].

Effect of co-administered drugs on the pharmacokinetics of pradigastat: As described earlier, pradigastat is metabolized via glucuronidation catalyzed by UGT1A1, UGT1A3, and UGT2B7. A clinical DDI study was conducted in 44 healthy subjects comprising two treatment cohorts, one with probenecid (a general UGT enzyme inhibitor; 1000 mg once daily) due to multiple UGTs involvement in pradigastat metabolic clearance; the other with atazanavir (UGT1A1/1A3 inhibitor; 400 mg once daily) as UGT1A1/1A3 are the primary contributors for pradigastat clearance. This study did not show any clinically relevant interaction with pradigastat and the UGT inhibitors in terms of pharmacokinetic parameters (Cmax and AUC) [30]. Although steady-state pradigastat exposure decreased (Cmax by 31% and AUCtau by 26%) when co-administered with atazanavir, the magnitude is considered small as compared to the variability, and thus not clinically relevant.

Digoxin and warfarin, the typical narrow therapeutic drugs, are also used in patients with cardiometabolic disease and hence potentially the same patient population for which pradigastat is indicated. Forty healthy subjects were randomized to two cohorts to receive either digoxin (0.25 mg once daily) or warfarin (25 mg single dose) in an open-label, three period sequential study [24]. Digoxin, when co-administered with pradigastat,



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Table 3: Summary of steady-state pharmacokinetic parameters of pradigastat in clinical studies.

Study Study type Subjects(n)

Pradigastat treatment

Pradigastat dose (mg)

Fed or fasted state

Tmax(hr)

Cmax(ng/mL)

AUClast(h.ng/mL)

Meyers (2015) [13] First-in-human

151512111512

Multiple ascending oral doses

1510101025

40% fat diet40% fat diet40% fat diet20% fat diet30% fat diet30% fat diet

8 (6-12)8 (2-12)10 (8-24)8 (0-24)10 (0-12)9 (0-10)

151 (41.2)831 (33.9)1,071 (31.9)1,606 (22.4)1,582 (36.5)1,943 (34.8)

2,457 (41.1)14,467 (33)20,103 (26.1)31,037 (21.7)27,577 (36.6)35,551 (37.7)

Meyers (2015) [6] Phase II 6 Once daily oral

dose

102040

Low-fat diet 1-10296 (111)950 (572)2,170 (1,300)

6,190 (2,660)18,000 (10,600)39,900 (24,100)

Mendoza (2015) [30]

DDI with probenecid or atazanavir

2121

Once daily oral dose 40

Treatment 1 hr before breakfast

1.5 (0-12)0.92 (0-4)

1,460 (631)1,680 (685)

22,700 (10,100)26,100 (9320)

Chen (2015) [25]

DDI with combination oral contraceptive 24 Once daily oral

dose 40

Low-fat meal (1 hr prior to treatment)

1 (0-23.9) 1,110 (378) 17,800 (6,190)

Kulmatycki (2015) [21] DDI with rosuvastatin 36 Once daily oral

dose 40 Low-fat diet 1 (0-24) 1,410 (855) 20,500 (10,900)

Yan (2014) [24]

DDI with digoxin or warfarin

2020

Once daily oral dose 40

Treatment 1 hr before breakfast

1 (0-24)20 (0.5-24)

1,260 (618)1,200 (710)

20,400 (10,100)19,800 (10,200)

Data presented as mean (SD) unless otherwise stated. Tmax (time to reach maximum concentration at steady state) presented as median (range). DDI: drug-drug interaction.Pradigastat monotherapy data presented for DDI studies.

Table 4: Effect of co-administered drug on pradigastat pharmacokinetics (row A) and effect of pradigastat on co-administered drug pharmacokinetics (row B)

Co-administered drug as

monotherapy

Pradigastat as monotherapy Combination therapy

Geometric Ratio (90% CI)

AUCtau or AUClast Cmax AUCinf

Rosuvastatin 10 mg qd Days 1-7 [21]

100 mg qd Days 1-3 then 40 mg qd Days 4-21

Rosuvastatin 10 mg qd + pradigastat 40 mg qd for 7 days

A 1.05 (0.98, 1.11) 0.98 (0.91, 1.06) -

B 0.95 (0.88, 1.01) 0.86 (0.79, 0.93) -

Digoxin 0.25 mg qd Days 1-7 [24]


Digoxin 0.25 mg qd + pradigastat 40 mg qd for 7 days

A 0.90(0.8, 1.0) 0.80(0.7, 0.9) -

B 1.0 (0.9, 1.1) 1.0 (0.9, 1.1) -

Warfarin 25 mg single dose [24]


Warfarin 25 mg + pradigastat 40 mg single dose

A 1.0 (0.9, 1.1) 1.0 (0.9, 1.1) -

B 1.0 (1.0, 1.0) (R-warfarin)

1.0 (0.9, 1.0) (R-warfarin)

1.0 (1.0, 1.1) (R-warfarin)

B 1.0 (1.0, 1.1) (S-warfarin)

1.0 (0.9, 1.0) (S-warfarin)

1.1 (1.0, 1.1)(S-warfarin)

LVG/EE 150/30 µg single dose [25]


LVG/EE 150/30 µg + pradigastat 40 mg single dose

A 0.97 (0.93, 1.02) 1.05 (1.00, 1.11) -

B 1.24 (1.15, 1.34) (LVG)

1.16 (1.06, 1.27) (LVG)

1.25 (1.16, 1.35) (LVG)

B 0.97 (0.93, 1.02) (EE) 0.97 (0.92, 1.02) (EE) 0.93 (0.87, 0.99) (EE)

Efavirenz 600 mg single dose [26]


Efavirenz 600 mg + pradigastat 40 mg single dose

A 1.05 (1.01, 1.09) 1.00 (0.94, 1.07) -

B 1.01 (0.94, 1.08) 1.04 (0.91, 1.17) 1.02 (0.95, 1.10)

Repaglinide 2 mg single dose [26]


Repaglinide 2 mg + pradigastat 40 mg single dose

A 1.02 (0.97, 1.08) 1.06 (0.99, 1.13) -

B 0.95 (0.89, 1.02) 0.88 (0.72, 1.08) 0.96 (0.89, 1.04)

Probenecid 1000 mg bid Days 1-3 [30]


Probenecid 1000 mg bid + pradigastat 40 mg qd for 3 days

A 1.00 (0.93, 1.09) 0.88 (0.80, 0.97) -

B 1.00 (0.97, 1.03) 0.99 (0.94, 1.04) -



J Drug Des Res 4(3): 1044 (2017) 8/10

Atazanavir 400 mg qd Days 1-5 [30]


Atazanavir 400 mg qd + pradigastat 40 mg qd for 5 days

A 0.74 (0.67, 0.82) 0.69 (0.62, 0.78) -

B 0.96 (0.79, 1.15) 0.91 (0.74, 1.12) -

Acetaminophen 1000 mg single dose with meal [20]

100 mg qd Days 1-3 then 40 mg qd Days 4-10 at 1 hr prior to meal

Acetaminophen 1000 mg (at -2 hr relative to meal time) + pradigastat 40 mg (at -1 hr prior to meal time)

B 0.99 (0.96, 1.03) 1.12 (1.04, 1.21)

Acetaminophen 1000 mg (at -1 hr relative to meal time) + pradigastat 40 mg (at -1 hr prior to meal time)

B 0.96 (0.93, 1.00) 1.06 (0.98, 1.14)

Acetaminophen 1000 mg (at 0 hr relative to meal time) + pradigastat 40 mg (at -1 hr prior to meal time)

B 0.97 (0.94, 1.01) 0.98 (0.90, 1.05)

Acetaminophen 1000 mg (at +1 hr relative to meal time) + pradigastat 40 mg (at -1 hr prior to meal time)

B 0.94 (0.90, 0.97) 0.92 (0.86, 1.00)

Acetaminophen 1000 mg (at +3 hr relative to meal time) + pradigastat 40 mg (at -1 hr prior to meal time)

B 0.97 (0.93, 1.00) 1.11 (1.03, 1.19)

AUCtau: area under the concentration-time curve over uniform dosing interval tau; Cmax: maximum measured concentration of drug in plasma; AUCinf: area under the concentration-time curve extrapolated to time infinity; qd: once a day (from the Latin quaque die); hr: hour; LVG/EE: levonorgestrel-ethinylestradiol

decreased the mean systemic pradigastat exposure by ~15% and was not considered clinically relevant. Similarly, concomitant administration with rosuvastatin, or oral contraceptives, did not alter the pharmacokinetics of pradigastat to any meaningful extent (Table 3, Figure 2).

Effect of pradigastat on the pharmacokinetics of co-administered drugs: In rodents, pharmacological inhibition and genetic deletion of DGAT1 resulted in delayed gastric emptying [31]. Consequently, as a potent DGAT1 inhibitor, pradigastat has the potential to delay gastric emptying and alter the absorption of concomitant medications around meal time in patients. This could considerably impact the efficacy of co-administered drugs, particularly those which require rapid absorption or whose absorption is dependent on the rate of gastric emptying (e.g., acetaminophen) [32].

In 25 healthy subjects, no change was observed in acetaminophen pharmacokinetics (Tmax, Cmax, or AUC) in the presence of steady-state pradigastat when acetaminophen was administered before (1 or 2 hr), with (0 hr) or after (3 hr) a meal, suggesting no impact of pradigastat on the rate and extent acetaminophen absorption; however, it was observed that the Tmax was modestly delayed (1.25 hr [0.75-2.0 hr]) when acetaminophen was administered in the presence of pradigastat 1 hr after a 2300 calorie meal compared with when administered alone with a meal [20], with no changes in peak or systemic plasma levels. The investigators noted that the delay in reaching peak acetaminophen absorption was more likely associated with the timing of acetaminophen administration relative to meal time than with pradigastat.

The efflux and uptake transporter proteins, BCRP, OATP1B1/3, and OAT3, have been shown to affect oral absorption, as well as hepatic and renal disposition of their substrate rosuvastatin, a statin commonly used for the treatment of hyperlipidemia [33]. Possible DDI between pradigastat (40 mg) and rosuvastatin (10 mg) were evaluated in 36 healthy volunteers in an open-label, single sequence study [21]. When co-administered with pradigastat, no change in rosuvastatin AUC and a 14% decrease in Cmax were observed, which was not considered clinically relevant. Therefore, it is unlikely that pradigastat would produce clinically significant DDIs with other co-medications that are substrates of BCRP, OATP1B1/3, or OAT3.

Similarly, no clinically relevant changes in the pharmacokinetics of the combination oral contraceptive Levora-28® (30µg ethinylestradiol and 150µg levonorgestrel) were observed when co-administered with pradigastat (40 mg once daily) in 24 healthy female subjects (Table 4). In the presence of steady-state pradigastat AUCinf, AUClast, and Cmax of levonorgestrel marginally increased by 25%, 24%and 16%, respectively [25]. However, these changes are unlikely to affect clinical efficacy of Levora-28®. Likewise, pradigastat did not have an effect on the pharmacokinetics of digoxin, probenecid or atazanavir, or the pharmacokinetics and pharmacodynamics of warfarin [24,30]. In summary, there were no clinically meaningful DDIs between pradigastat and any of the drugs evaluated, thus dose adjustments are not required.

Effect of pradigastat on post-prandial and fasting triglyceride: To assess the effects of pradigastat on post-prandial and fasting triglyceride levels in overweight or obese



J Drug Des Res 4(3): 1044 (2017) 9/10

healthy subjects, a meal tolerance test was used. The first-in-human study evaluated pharmacodynamics of pradigastat administered at single and multiple doses [13]. Pradigastat suppressed post-prandial TGs over 9 hrs after a high-fat meal test dose dependently following both single and multiple dose administration. Post-prandial glucose and insulin were lower in the pradigastat-treated subjects, while plasma glucagon-like peptide-1 levels were elevated.

In an open-label clinical study, the TG-lowering efficacy of pradigastat was assessed in patients with FCS [6]. Patients had a 1 week low fat diet run-in period before baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 and 10 mg, respectively). In this study, pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting TG over 21 days of treatment. Drug treatment also led to substantial reductions in post-prandial TG and apolipoprotein B48 (apoB48). Together, these studies suggest that pradigastat is associated with lower post-prandial TGs in FCS patients.

Effect of pradigastat on cardiac conduction and repolarization: A supratherapeutic plasma pradigastat exposure was used to assess the effects of the drug on the corrected QT interval (QTc) in healthy subjects [22]. IV infusion (115 mg) of pradigastat was used in order to provide increased plasma exposure and avoid potential GI tolerability issues associated with oral dosing in this randomized, placebo- and positive-controlled (moxifloxacin), double-blind, double-dummy, parallel-group study. During the infusion of pradigastat there was a decrease in the baseline corrected QTc interval in the pradigastat group, after which there was no increase in the placebo-corrected time-matched change from baseline in QTcF interval (∆∆QTcF), which was maintained at or near zero. The upper 90% CI of the mean ∆∆QTcF was below the 10 millisecond threshold for drug effect; meanwhile, moxifloxacin increased the ∆∆QTcF with the lower 90% CI exceeding the 5 millisecond threshold in multiple time points.

Supratherapeutic exposure with a mean Cmax of 8650 ng/mL (~4x Cmax,ss at 40 mg) was achieved through IV infusion (115 mg) of pradigastat. No statistically significant correlation was found between the time matched baseline corrected change in QTcF (∆QTcF) and pradigastat plasma concentrations. Thus, pradigastat did not increase the QTc interval in humans, and hence does not likely affect the risk of proarrhythmia associated with prolonged QTc.

Effect of pradigastat on photosensitivity: Pradigastat has been shown to induce mild photosensitivity reactions in mice when given at a high dose with supra-therapeutic exposure. A clinical study was designed to determine if pradigastat induced photosensitivity in humans at a therapeutic exposure associated with the highest clinical dose of 40 mg per day [34]. A loading dose regimen of 100 mg daily for three days followed by 40 mg daily for seven more days was administered. At high therapeutic exposures of pradigastat, photosensitivity was not induced either under conditions of enhanced UVA exposure (up to 25 J/cm2) or combined full range UVB/UVA exposure (limited by the erythmogenic potential). Compared with placebo, there

was no significant increase in the photosensitivity index and no significant lowering of minimal erythemal doses at any of the time points measured. Furthermore, there was no significant difference between pradigastat and placebo in erythema scores or superficial skin effects.

CONCLUSIONOverall, clinical pharmacokinetic studies support pradigastat

administration without regard to food intake. It is anticipated that no dose adjustment is needed for patients with renal impairment and patients with mild or moderate hepatic impairment. The primary pathway for pradigastat metabolism is glucuronidation, with little contribution from CYP enzymes. No clinically relevant drug-drug interaction was identified, and no impact of gender, race, age, weight on the pharmacokinetics of pradigastat was observed; therefore, no dose adjustment is needed for any of these conditions.

CONFLICT OF INTERESTThis study was funded by Novartis Institutes for BioMedical

Research, East Hanover, NJ, USA. JC and GS are employees of Novartis Institutes for BioMedical Research, East Hanover, NJ, USA. DK is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. DM was employed with Novartis when the study was conducted. JY is an employee of Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

ACKNOWLEDGEMENTSThe authors thank Ciara Kelly, PhD, Jackie L. Johnson, PhD, and

Swathi Seshadri, PhD of Novartis Ireland Limited, Dublin, Ireland for providing medical writing support and editorial support, which was funded by Novartis Pharma AG, Basel, Switzerland in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

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Chen J, Meyers D, Keefe D, Yu J, Sunkara G (2017) Clinical Pharmacokinetics of Pradigastat, a Novel Diacylglycerol Acyltransferase 1 Inhibitor. J Drug Des Res 4(3): 1044.

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