Comparative pharmacokinetics and bioavailability of monomethyl fumarate following a single oral dose of Bafiertam® (monomethyl fumarate) versus Vumerity® (diroximel fumarate).

BACKGROUND: Bafiertam® (monomethyl fumarate [MMF]) and Vumerity® (diroximel fumarate [DRF]) are two FDA approved drug products for the treatment of relapsing forms of multiple sclerosis (MS) to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Vumerity® is a prodrug of MMF which requires enzymatic conversion of DRF to the active drug MMF, the moiety responsible for the therapeutic efficacy; whereas Bafiertam® contains MMF, providing the active drug directly without any need for enzymatic conversion. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and relative bioavailability of MMF from oral administration of two Bafiertam® capsules each containing 95 mg of MMF in comparison to two Vumerity® capsules each containing 231 mg of DRF, the therapeutic doses of each product. METHODS: This was a single-dose, open-label, randomized, 2-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Forty-four healthy male or female subjects were planned to receive each of the two treatments to assure 40 completed dosing: a single dose of 2  ×  95 mg Bafiertam® capsules and a single dose of 2  ×  231 mg Vumerity® capsules under fasting conditions in a randomized crossover fashion. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. MMF pharmacokinetic [PK] parameters were calculated and included maximum observed concentration (Cmax), time to reach Cmax (tmax), apparent half-life of MMF in plasma (t1/2), AUC0-t which is the area under the plasma concentration vs. time curve (AUC) from time zero (dosing time) to the last time point, t, with quantifiable MMF concentration, and AUC0-inf which is AUC0-t plus the extrapolated AUC from time t to infinity. RESULTS: Forty-one subjects completed the study as planned. MMF in Bafiertam® capsules was well and readily absorbed with a median tmax occurring at 4 h post dose, approximately 1 h later than that of Vumerity® capsules. However, the mean MMF Cmax from Bafiertam® (1969 ng/mL) was higher than that from Vumerity® (1121 ng/mL). The mean MMF AUC0-t and AUC0-inf from Bafiertam® (3503 and 3531 h*ng/mL) were also higher than those from Vumerity® (3123 and 3227 h*ng/mL), respectively. The geometric least-squares mean (GLSM) ratios (90% confidence interval), Bafiertam® vs. Vumerity®, for MMF Cmax, AUC0-t and AUC0-inf were 181.8 (158.2 - 208.8)%, 116.8 (107.9-126.5)% and 113.8 (105.3 - 123.0)%, respectively.  Both products were safe and well tolerated, as expected, with flushing being the most common adverse event for both products. CONCLUSIONS: The mean MMF AUC0-t and AUC0-inf were 14-17% higher after administration of Bafiertam® as compared to Vumerity® at their respective therapeutic doses under fasting conditions, however, this difference was not statistically or clinically significant. Although more clinical studies would be needed before making strong recommendations, results of this study may help with selecting appropriate fumarate products, especially when administering the product with food is clinically recommended.

Pharmacokinetics and Bioavailability of Monomethyl Fumarate Following a Single Oral Dose of Bafiertam™ (Monomethyl Fumarate) or Tecfidera® (Dimethyl Fumarate).

BACKGROUND: Tecfidera® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy. OBJECTIVE: The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera® capsule containing 240 mg of DMF, a prodrug of MMF. METHODS: This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC0-t which is the area under the plasma concentration-time curve (AUC) from time zero (dosing time) to the last time point, t, with measurable analyte concentration, and AUC0-inf, which is AUC0-t plus the extrapolated AUC from time t to infinity. RESULTS: The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18-101.64), 96.35% (91.81-101.12), and 104.84% (95.54-115.05) for AUC0-t, AUC0-inf, and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera®, respectively. CONCLUSIONS: Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera® DR 240 mg capsule. CLINICAL TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020.

Monomethyl fumarate has better gastrointestinal tolerability profile compared with dimethyl fumarate.

BACKGROUND: Monomethyl fumarate (MMF) is the pharmacologically active metabolite of dimethyl fumarate (DMF). MMF formulated as Bafiertam™ 190 mg and DMF formulated as Tecfidera 240 mg deliver bioequivalent exposure of MMF and therefore possess the same efficacy/safety profiles. DMF is a widely used oral treatment for relapsing-remitting forms of multiple sclerosis (RRMS) but is limited in some patients, primarily female, by issues with gastrointestinal (GI) tolerability. METHODS: This was a randomized, double-blind, head-to-head, 5-week study evaluating the GI tolerability of MMF 190 mg vs DMF 240 mg, administered twice daily in healthy subjects, using a derivative of the self-administered Modified Overall Gastrointestinal Symptom Scale (MOGISS). Subjects were stratified (3:1, female:male) and randomized (1:1) to the treatments. The primary endpoint was the Area Under the Curve (AUC) in each of the individual symptoms in the MOGISS over the 5-week treatment period. Other endpoints included the AUC over the 5-week treatment period in the MOGISS composite and total scores; duration and severity of GI events; Number and percentage of subjects reporting GI events during the overall treatment period, and assessment of safety/tolerability. RESULTS: Inferential analysis of the hierarchical testing of overall treatment differences in each MOGISS symptom AUC occurred in a predefined sequence starting with Abdominal Pain. For each symptom, LSMean AUC values were lower for MMF than DMF, however, the first primary endpoint, Abdominal Pain, was not statistically different between treatments; thus, all subsequent statistical analyses were considered exploratory. The side effects and safety profiles observed were consistent with the known profiles of DMF, with no new or unique safety concerns noted. CONCLUSIONS: Bafiertam showed an improved gastrointestinal tolerability profile compared with Tecfidera, with less severe GI events and fewer days of self-assessed GI symptoms, fewer GI adverse events, and lower discontinuation rates because of GI adverse events.

A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis.

UNLABELLED: In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3-cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group. CONCLUSION: GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.

Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients.

OBJECTIVES: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. DESIGN: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. METHODS: Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. RESULTS: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. CONCLUSIONS: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.

Pharmacokinetic and pharmacodynamic characteristics of emtricitabine support its once daily dosing for the treatment of HIV infection.

Emtricitabine (FTC) is a potent deoxycytidine nucleoside analogue that was recently approved for the treatment of HIV infection. Emtricitabine is activated by intracellular phosphorylation to its 5'-triphosphate (FTC5'-TP), a competitive inhibitor of the HIV reverse transcriptase (RT). Early clinical studies incorporating pharmacokinetic-pharmacodynamic (PK-PD) analyses provided a sound rationale for developing FTC as a once daily drug. A short-term open-label monotherapy trial in therapy naive HIV-infected subjects evaluated various dosage regimens of FTC, i.e., 25, 100, and 200 mg qd and/or bid, with serial measurements of plasma HIV RNA, plasma FTC, and intracellular (PBMC) FTC-5'-TP levels over the 14 days of treatment. PK data were augmented by other steady-state studies, one in healthy volunteers and the other in HIV-infected patients receiving 200 mg FTC qd, with measurements of plasma FTC and/or intracellular FTC-5'-TP levels. Correlation between anti-HIV activity and FTC-5'-TP levels was examined with dose- and concentration-response relationships determined. The once daily dosing schedule is supported by the relatively long half-lives of plasma FTC (8-10 hr) and PBMC FTC-TP (39 hr) and the high plasma FTC and PBMC FTC-5'-TP concentrations. HIV RNA suppression (PD) correlates well with PBMC FTC-5'-TP levels (PK), both reaching a plateau at doses > or = 200 mg/day. The PK and PD characteristics of FTC demonstrate that it is a once daily nucleoside RT inhibitor.

Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in human immunodeficiency virus-infected patients.

We conducted a randomized, open-label, 10-day study that compared the antiretroviral activity of emtricitabine (FTC) 25, 100, and 200 mg once daily and lamivudine (3TC) 150 mg 2 times/day in 82 human immunodeficiency virus (HIV)-infected patients with virus loads >5000 and <100,000 copies/mL who were naive for 3TC and abacavir. All FTC doses demonstrated potent antiretroviral activity. Significantly greater virus suppression was seen at the 200 mg/day dose of FTC than with the lower FTC doses and/or 3TC (P=.02, P=.04, and P=.04, respectively). At the 200 mg/day dose, FTC produced a 1.7-log10 mean reduction in virus load. Trough FTC levels at the 200 mg/day dose exceeded the in vitro 90% inhibitory concentration dose for FTC by 5-fold. The long plasma half-life and the superior antiviral activity versus 3TC of the 200 mg/day FTC dose confirmed the results of other studies and led to the selection of this dose for subsequent therapeutic trials.

Reproductive toxicology profile of emtricitabine in mice and rabbits.

Reproductive and developmental toxicology studies were conducted with emtricitabine, a nucleoside analog in development for treatment of human immunodeficiency virus (HIV) (Phase III) and hepatitis B (HBV) (Phase III) infections. Oral doses up to 1000 mg/kg/day provided daily area under the curve (AUC(0-->24)) exposure to pregnant animals approximately 60- (mice) to 120-fold (rabbits) higher than that in humans at the recommended dose of 200 mg given once per day. In a mouse fertility study, emtricitabine had no effect on fertility, sperm count, or early embryonic development. There was no increased incidence of malformations in mouse and rabbit embryofetal toxicology studies. The average ratio for concentration of emtricitabine in fetal plasma divided by concentration in maternal plasma was approximately 0.40 in mice and 0.50 in rabbits, a finding that indicates significant exposure of the fetuses to emtricitabine. The development and fertility of F(1) progeny were unaffected by emtricitabine in a mouse pre- and post-natal study. These data demonstrate a favorable pre-clinical reproductive safety profile for emtricitabine.