Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Exposure-Response
In dose-ranging studies that evaluated doses of 400 mg twice daily and twice daily doses of two and three times the recommended dose, no exposure-response relationship was observed for viral load or probability of unquantifiable plasma CMV DNA.
In Phase 3 Trial 303 that evaluated a maribavir dose of 400 mg twice daily, increasing maribavir exposure was not associated with increased probability of confirmed plasma CMV DNA < LLOQ (lower limit of quantification) at Week 8.
Cardiac Electrophysiology
At three times the recommended dose (approximately twice the peak concentration observed following the recommended dose), LIVTENCITY does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic Properties

12.3 Pharmacokinetics
LIVTENCITY pharmacological activity is due to the parent drug. Following oral administration, plasma maribavir exposure (Cmax and AUC) increased approximately dose-proportionally following a single dose of 50 to 1600 mg (0.125 to four times the recommended dose) and multiple doses up to 2400 mg per day (three times the recommended daily dose). Maribavir PK is time-independent. With twice-daily dosing, steady state is reached within 2 days, with mean accumulation ratios of C max and AUC ranging from 1.37 to 1.47.
The pharmacokinetic properties of maribavir following administration of LIVTENCITY are displayed in Table 5. The multiple-dose pharmacokinetic parameters are provided in Table 6.



Table 5: Pharmacokinetic Properties of Maribavir

Absorptiona
Tmax (h), median                                                1.0 to 3.0 Distribution
Mean apparent steady-state volume of distribution               24.9
(Vss, L)
% bound to human plasma proteins                                98.0 across the concentration range of 0.05-200 μg/mL Blood-to plasma ratio                                           1.37
Elimination
Major route of elimination                                      Hepatic metabolism Half-life (t1/2) in transplant patients (h), mean               4.32
Oral clearance (CL/F) in transplant patients (L/h),             2.67 mean
Metabolism
Metabolic pathwaysb                                             CYP3A4 (major) and CYP1A2 (minor) Excretion
% of dose excreted as total 14C (unchanged drug) in             61 (<2) urinec
% of dose excreted as total 14C (unchanged drug) in             14 (5.7) fecesc a
When taken orally with a high fat, high caloric meal vs fasted, the AUC0‑∞ and Cmax (geometric mean ratio [90% CI] of maribavir are 0.878 [0.843, 0.915] and 0.716 [0.671, 0.764], respectively.
b
In vitro studies have shown that maribavir is biotransformed into a major circulating inactive metabolite: VP 44469 (N-dealkylated metabolite), with a metabolic ratio of 0.15 - 0.20. Multiple UGT enzymes, namely UGT1A1, UGT1A3, UGT2B7, and possibly UGT1A9, are involved in the glucuronidation of maribavir in humans, however, the contribution of glucuronidation to the overall clearance of maribavir is low based on in vitro data.
c
Dosing in mass balance study: single-dose administration of [14C] maribavir oral solution 400 mg containing 200 nCi of total radioactivity.
Table 6: Multiple-Dose Pharmacokinetic Parameters of Maribavir
Geometric Mean (% CV)a
AUC0-taub                                   Cmax                                        Ctau (µg•h/mL)                                  (µg/mL)                                     (µg/mL) 142 (48.5%)                               20.1 (35.5%)                                5.43 (85.9%) CV=Coefficient of Variation; Cmax=Maximum concentration; AUC0-tau=Area under the time concentration curve over a dosing interval; Ctau=Concentration at the end of a dosing interval.
a
Pharmacokinetic parameter values based on post-hoc estimates from maribavir population pharmacokinetic model in transplant patients with CMV receiving 400 mg of LIVTENCITY twice daily with or without food.
b tau is maribavir dosing interval: 12 hours.

Specific Populations
There were no clinically significant differences in the pharmacokinetics of maribavir based on age (18-79 years), gender, race (Caucasian, Black, Asian, or others), ethnicity (Hispanic/Latino or non-Hispanic/Latino), body weight (36 to 141 kg), transplant type, mild to severe renal impairment (measured creatinine clearance ranging from 12 to 70 mL/min), or mild to moderate hepatic impairment (Child-Pugh Class A or B).
Pediatric Patients
The pharmacokinetics of maribavir in patients less than 18 years of age have not been evaluated.
Using modeling and simulation, the recommended dosing regimen is expected to result in comparable steady-state plasma exposures of maribavir in patients 12 years of age and older and weighing at least 35 kg as observed in adults [see Use in Specific Populations (8.4)].
Drug Interactions
Based on in vitro studies, the metabolism of maribavir is not mediated by CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A5, UGT1A4, UGT1A6, UGT1A10, or UGT2B15. The transport of maribavir is not mediated by organic anion transporting polypeptide (OATP)1B1, OATP1B3, or bile salt export pump (BSEP).
At clinically relevant concentrations, clinically significant interactions are not expected when LIVTENCITY is coadministered with substrates of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP2D6, CYP3A4; uridine diphosphate-glucuronosyltransferase (UGT)1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7; P-gp; BSEP; multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2; OATP1B1 and OATP1B3. In a clinical drug-drug interaction cocktail study, coadministration with maribavir had no effect on substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
Drug interaction studies were performed with LIVTENCITY and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of coadministration of other drugs on the pharmacokinetics of maribavir are summarized in Table 7, and the effects of maribavir on the pharmacokinetics of coadministered drugs are summarized in Table 8.
Dosing recommendations as a result of established and other potentially significant drug-drug interactions with LIVTENCITY are provided in Table 4 [see Drug Interactions (7.3)].
Table 7: Changes in Pharmacokinetics of LIVTENCITY in the Presence of Coadministered Drugs 
Geometric Mean Ratio (90% CI) of LIVTENCITY PK with/without
LIVTENCITY                              Coadministered Drug
Coadministered Drug and Regimen                             N
Regimen                                 [No Effect=1.00]
AUC             Cmax           Ctauc
Anticonvulsants
800 mg
400 mg                                          1.40            1.53           1.05 Carbamazepinea                       twice daily / 400 mg   200 once daily                                   (1.09, 1.67)    (1.22, 1.79)   (0.71, 1.40) twice daily
1,200 mg
100 mg                                          1.80            2.17           0.94 Phenobarbitala                      twice daily / 400 mg   200 once daily                                   (1.18, 2.35)    (1.69, 2.57)   (0.22, 1.97) twice daily
1,200 mg
300 mg                                          1.70            2.05           0.89 Phenytoin   a                      twice daily / 400 mg   200 once daily                                   (1.06, 2.46)    (1.49, 2.63)   (0.26, 2.04) twice daily
Antimycobacterials


600 mg                 400 mg                          0.40                 0.61               0.18 Rifampin             once daily            twice daily          14       (0.36, 0.44)         (0.52, 0.72)       (0.14, 0.25) Antifungals
400 mg                 400 mg                          1.53                 1.10 Ketoconazole                                                      19                                                    - single dose            single dose                   (1.44, 1.63)         (1.01, 1.19) Antacids
Aluminum hydroxide
20 mLb                 100 mg                          0.89                 0.84 and magnesium                                                      15                                                    - single dose            single dose                   (0.83, 0.96)         (0.75, 0.94) hydroxide antacid a
Based on physiologically based pharmacokinetic modeling results from 10 trials of 20 subjects each. The maribavir dosing regimen and geometric mean ratios (5th percentile, 95th percentile) correspond to dose-adjusted maribavir with inducer vs 400 mg twice daily without inducer.
b
Containing 800 mg aluminum hydroxide and 800 mg magnesium hydroxide.
c tau is maribavir dosing interval: 12 hours.

Table 8: Drug Interactions: Changes in Pharmacokinetics for Coadministered Drug in the Presence of 400 mg Twice Daily LIVTENCITY

Geometric Mean Ratio (90% CI) of Coadministered Drug PK with/without
Coadministered Drug and Regimen                             N                 LIVTENCITY [No Effect=1.00]
AUC                Cmax             Ctau
Immunosuppressants
1.51               1.38            1.57
Tacrolimus        stable dose, twice daily (total daily dose: 0.5-16 mg)   20 (1.39, 1.65)       (1.20, 1.57)    (1.41, 1.74)
P-gp substrate
0.5 mg                                      1.21               1.25                - Digoxin                                                                  18 single dose                               (1.10, 1.32)       (1.13, 1.38) 
12.4 Microbiology
Mechanism of Action
The antiviral activity of maribavir is mediated by competitive inhibition of the protein kinase activity of human CMV enzyme pUL97, which results in inhibition of the phosphorylation of proteins. Maribavir inhibited wild- type pUL97 protein kinase in a biochemical assay with an IC 50 value of 0.003 µM. Maribavir and its 5′-mono- and 5′-triphosphate derivatives at 100 μM had no significant effect on the incorporation of deoxynucleoside triphosphates by human CMV DNA polymerase. At a concentration of 100 µM, neither maribavir nor its 5′-triphosphate derivative inhibited CMV DNA polymerase delta, however the 5′-monophosphate derivative inhibited incorporation by polymerase delta of all 4 natural dNTPs by approximately 55%.
Antiviral Activity
Maribavir inhibited human CMV replication in virus yield reduction, DNA hybridization, and plaque reduction assays in human lung fibroblast cell line (MRC-5), human embryonic kidney (HEK), and human foreskin fibroblast (MRHF) cells. The EC50 values ranged from 0.03 to 2.2 µM depending on the cell line and assay endpoint. The cell culture antiviral activity of maribavir has also been evaluated against CMV clinical isolates.
The median EC50 values were 0.1 μM (n=10, range 0.03-0.13 μM) and 0.28 μM (n=10, range 0.12-0.56 μM) using DNA hybridization and plaque reduction assays, respectively. No significant difference in EC50 values 

across the four human CMV glycoprotein B genotypes (N=2, 1, 4, and 1 for gB1, gB2, gB3, and gB4, respectively) was seen.
Combination Antiviral Activity
When maribavir was tested in combination with other antiviral compounds, antagonism of the antiviral activity was seen in combination with ganciclovir. No antagonism was observed with cidofovir, foscarnet, letermovir and rapamycin at the drugs EC50 values. The pUL97 kinase activity inhibited by maribavir is necessary to activate valganciclovir/ganciclovir.
Treatment Effect in CMV Glycoprotein B (gB) Subtypes
In Trial 303, the primary endpoint response rates for LIVTENCITY across CMV gB subtypes 1, 2, 3, 4, and 5 were 65% (55/85), 39% (22/57), 54% (22/41), 67% (14/21), and 64% (7/11), respectively. The primary endpoint response rates for IAT across CMV gB subtypes 1, 2, 3, 4, and 5 were 28% (15/53), 27% (4/15), 11% (2/19), 20% (2/10), and 17% (1/6), respectively [see Clinical Studies (14)].
Viral Resistance
In Cell Culture
Selection of maribavir resistant virus in cell culture and genotypic plus phenotypic characterization of these has identified amino acid substitutions that confer reduced susceptibility to maribavir. Substitutions identified in pUL97 include L337M, V353A, L397R, T409M, and H411L/N/Y. These substitutions confer reductions in susceptibility that range from 3.5-fold to >200-fold. Substitutions were also identified in pUL27:R233S, W362R, W153R, L193F, A269T, V353E, L426F, E22stop, W362stop, 218delC, and 301-311del. These substitutions confer reductions in susceptibility that range from 1.7- to 4.8-fold.
In Clinical Studies
In Phase 2 Study 202 evaluating maribavir in 120 hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) recipients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of a select region of pUL97 (amino acids 270 to 482) and pUL27 (amino acids 108 to 424) was performed on 34 paired virologic failure samples. There were 25 patients with treatment-emergent maribavir resistance- associated substitution(s) in pUL97 F342Y (4.5-fold reduction in susceptibility), T409M (78-fold reduction), H411L/Y (69- and 12-fold reduction) and/or C480F (224-fold reduction).
In Phase 3 Study 303 evaluating maribavir in patients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of the entire coding regions of pUL97 and pUL27 was performed on 134 paired sequences from maribavir-treated patients. The treatment-emergent pUL97 substitutions F342Y (4.5-fold), T409M (78-fold), H411L/N/Y (69-, 9-, and 12-fold, respectively), and/or C480F (224-fold) were detected in 58 subjects (47 subjects were on-treatment failures and 11 subjects were relapsers). One subject with the pUL27 L193F substitution (2.6-fold reduced susceptibility to maribavir) at baseline did not meet the primary endpoint.
Cross-Resistance
Cross-resistance has been observed between maribavir and ganciclovir/valganciclovir in cell culture and in clinical studies.
pUL97 valganciclovir/ganciclovir resistance-associated substitutions F342S/Y, K355del, V356G, D456N, V466G, C480R, P521L, and Y617del reduce susceptibility to maribavir >4.5-fold. Other vGCV/GCV resistance pathways have not been evaluated for cross-resistance to maribavir. pUL54 DNA polymerase substitutions conferring resistance to vGCV/GCV, cidofovir, or foscarnet remained susceptible to maribavir.
Substitutions pUL97 F342Y and C480F are maribavir treatment-emergent resistance-associated substitutions that confer >1.5-fold reduced susceptibility to vGCV/GCV, a fold reduction that is associated with phenotypic resistance to vGCV/GCV. The clinical significance of this cross-resistance to vGCV/GCV for these substitutions has not been determined. Maribavir resistant virus remained susceptible to cidofovir and foscarnet.
Additionally, there are no reports of any pUL27 maribavir resistance-associated substitutions being evaluated for vGCV/GCV, cidofovir, or foscarnet cross-resistance. Given the lack of resistance-associated substitutions for these drugs mapping to pUL27, cross-resistance is not expected for pUL27 maribavir substitutions.