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Pharmacodynamics

29 evidence topics · 14 sources

Exposure-response: prescribing information

“No exposure-response relationship was identified between steady-state plasma pritelivir exposures at 100 mg once daily and the occurrence of all lesions healed by Day 28.” (opens the prescribing information at this quote)

Cardiac electrophysiology: prescribing information

“At 4 times the recommended maintenance pritelivir dose, clinically significant QTc interval prolongation was not observed.” (opens the prescribing information at this quote)

Doses evaluated in the thorough QT trial

“In Group 1, 32 male and female subjects (at least 12 subjects per sex) received a loading dose of 400 mg pritelivir on Day 1.” (opens the source at this quote in a new tab)
“Afterwards they received 100 mg pritelivir qd from Day 2 to 6 and 400 mg pritelivir qd from Day 7 to 16.” (opens the source at this quote in a new tab)

Inhibition of hERG potassium channels in vitro

“A 50% inhibitory concentration of approximately 160 μM was determined which is more than 100-fold higher than the maximum observed plasma concentration at therapeutic doses after correction for protein binding.” (opens the source at this quote in a new tab)
“Therefore, the interaction between pritelivir and hERG potassium channels is of negligible clinical relevance in humans.” (opens the source at this quote in a new tab)

Secondary pharmacology: inhibition of carbonic anhydrases

“Primary sulfonamides are well-known for their affinity to carbonic anhydrases (CAs).” (opens the source at this quote in a new tab)
“Pritelivir is an inhibitor of human CAs in vitro with Ki values ranging from 12.8 to 474.0 nM against the various CA isoforms, determined by assaying the CA-catalyzed CO2 hydration activity using phenol red as an indicator.” (opens the source at this quote in a new tab)
“Of note, in an esterase assay investigating the activity against the human CA isoform II, IC50 values of 2–5 μmol/L were reported.” (opens the source at this quote in a new tab)
“In line with this, clinical trials revealed no adverse effects attributable to sequelae of CA inhibition such as electrolyte disturbances.” (opens the source at this quote in a new tab)

Dose-dependent reduction of genital HSV-2 shedding in the phase 2 dose-finding trial

“HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly.” (opens the source at this quote in a new tab)
“The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose.” (opens the source at this quote in a new tab)
“When HSV was detected, the median log10 number of HSV DNA copies was 5.1 with placebo, 4.5 with 5 mg of pritelivir daily, 3.6 with 25 mg daily, 2.4 with 75 mg daily, and 3.6 with 400 mg weekly (P<0.001 for the comparisons of placebo with doses of pritelivir of 25 mg or more) (Table 2 and Figure 1B).” (opens the source at this quote in a new tab)
“The effect was dose-related, with a daily dose of 75 mg having the greatest antiviral effect.” (opens the source at this quote in a new tab)
“Furthermore, at this dose, pritelivir reduced the quantity of HSV in breakthrough shedding by more than 98%.” (opens the source at this quote in a new tab)
“Although the HSV shedding rate was reduced by more than 85% at the highest doses of pritelivir, as compared with placebo, some breakthrough shedding remained.” (opens the source at this quote in a new tab)

Genital HSV-2 shedding at 100 mg daily compared with valacyclovir

“In intent-to-treat analyses, HSV shedding was detected in 2.4% (173 of 7276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7453) during valacyclovir treatment (relative risk [RR], 0.42; 95% CI, 0.21 to 0.82; P = .01).” (opens the source at this quote in a new tab)
“In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, −0.1; 95% CI, −0.6 to 0.5; P = .83).” (opens the source at this quote in a new tab)

Mathematical model of HSV-2 shedding against dose: structure and inputs

“We designed a mathematical model that synthesizes pharmacokinetics, pharmacodynamics and viral pathogenesis concepts to simulate the activity of pritelivir, a DNA helicase-primase inhibitor that targets herpes simplex virus.” (opens the source at this quote in a new tab)
“Our simulations recapitulate detailed viral kinetic shedding features in five dosage arms of a phase 2 clinical trial.” (opens the source at this quote in a new tab)
“The PD model (Methods and Supplement) includes three parameters: percent of drug unbound to protein (2.8%), in vivo EC50 and the Hill coefficient (m).” (opens the source at this quote in a new tab)
“In vivo EC50 is the unbound plasma drug concentration at which viral replication is inhibited 50% in infected persons.” (opens the source at this quote in a new tab)

Mathematical model: in vivo EC50 estimate and time above it by dose

“Published in vitro EC50 values indicate variability in viral sensitivity to pritelivir amongst isolates (mean=11.7 ng/mL, range=3.6–26.1)” (opens the source at this quote in a new tab)
“In vivo EC50 values between 50 and 70 ng/mL provided best fit (Fig 4a).” (opens the source at this quote in a new tab)
“Thus, our in vivo EC50 estimate is 2–15 fold higher than in vitro measures.” (opens the source at this quote in a new tab)
“The in vivo EC50 estimate is higher than trough and peak pritelivir concentrations for 5 and 25 mg daily dosing (Fig 4b,c).” (opens the source at this quote in a new tab)
“Unbound plasma pritelivir levels exceed the in vivo EC50 for the entire dosing interval at 75 mg (Fig 4d) and 40% of the time at 400 mg weekly (Fig 4e).” (opens the source at this quote in a new tab)
“High copy shedding occurred exclusively with unbound drug levels below the in vivo EC50.” (opens the source at this quote in a new tab)
“It appears that the Hill coefficient has little impact on shedding rate in this study because even in the 75 mg daily arm, unbound drug values only exceed the in vivo EC50 two-fold.” (opens the source at this quote in a new tab)

Mathematical model: predicted and observed shedding at higher doses

“While 75 mg daily achieved an 85% reduction in shedding rate versus placebo and was the most effective dose in the trial, we observed decreased shedding rates at low and high viral quantities with increasing simulated dose and dosing frequency (Fig 8a).” (opens the source at this quote in a new tab)
“Up to 96% reduction versus the placebo shedding rate was reached at 150 mg per day, and average daily cumulative dose regardless of dosing frequency was highly predictive of simulated and observed shedding rate (Fig 8b).” (opens the source at this quote in a new tab)
“We performed 10 simulations of a 90 participant trial at 100 mg daily and obtained a median shedding rate of 1.7% (range: 0.6% – 2.7%).” (opens the source at this quote in a new tab)
“In a subsequent trial of 91 participants who performed swabs every 6 hours in which pritelivir 100 mg daily was compared to valacyclovir 500 mg daily, the shedding rate on pritelivir was 2.4% (173 of 7276 swabs positive for HSV DNA)” (opens the source at this quote in a new tab)

Mathematical model: effect on viral spread between sites

“While pritelivir directly inhibits replication in epithelial cells, our model indicates that pritelivir also indirectly limits downstream viral spread from neurons to genital keratinocytes, within genital ulcers, and from ulcer to new mucosal sites of infection.” (opens the source at this quote in a new tab)
“With daily dosing, pritelivir concentrations reach a relative steady-state due to its longer half-life (Fig 4b–d): accordingly, the percent of episodes associated with secondary seeding decreased at higher doses (placebo: 25.7%, 5 mg: 26.0%, 25 mg: 19.1%, 75 mg: 9.7%, 400 mg weekly: 13.2%) (Fig 6d).” (opens the source at this quote in a new tab)

HSV DNA in lesion swabs during treatment of refractory infection in PRIOH-1

“HSV DNA obtained from lesion swabs collected during study visits in the treatment period and at the end-of-treatment visit was detected less often in the pritelivir arm (34.8%) than the foscarnet arm (50.0%), but the difference was not significant (P = .42)” (opens the source at this quote in a new tab)

“9 days on pritelivir vs 21 days on ICT” (opens the source at this quote in a new tab)
“Hazard ratio 1.76 (HR >1 favors pritelivir); 95% CI, 0.98-3.16; p = 0.058” (opens the source at this quote in a new tab)
“Observed treatment effects with pritelivir align with efficient control of viral replication and reduction in viral burden” (opens the source at this quote in a new tab)

Animal models: efficacy stated in the first report of the compound

“BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease.” (opens the source at this quote in a new tab)

Murine lethal challenge model: dose protecting 50% of animals

“BAY 57-1293 and several compounds currently used for the treatment of herpes infections in humans were tested in escalating doses, and the individual dose at which 50% of the infected animals survived (ED50) was calculated by nonlinear regression.” (opens the source at this quote in a new tab)
“With an ED50 of 0.5 mg/kg of body weight t.i.d. against HSV-1 and HSV-2, BAY 57-1293 was the most potent compound tested.” (opens the source at this quote in a new tab)
“The rank order of the potencies was BAY 57-1293 > ganciclovir > valacyclovir > famciclovir > acyclovir > brivudine.” (opens the source at this quote in a new tab)

Murine lethal challenge model: ED50 by compound in mg/kg

Compound	HSV-1	HSV-2
BAY 57-1293	“0.5”	“0.5”
Ganciclovir	“2.5”	“1.0”
Valacyclovir	“17”	“15”
Famciclovir	“17”	“24”
Acyclovir	“22”	“16”
Brivudin	“37”	“>60”

Murine and rat models: viral burden, rebound after treatment, and once-daily dosing

“In all organs and at all time points tested, viral titers were strongly reduced in the BAY 57-1293-treated group compared to the titers in the placebo-treated group.” (opens the source at this quote in a new tab)
“Most importantly, in contrast to the findings for the valacyclovir-treated animals, animals treated with BAY 57-1293 did not show a recurrence of infectious virus in the trigeminal ganglia or brain cortex after the cessation of antiviral therapy (Fig. 2).” (opens the source at this quote in a new tab)
“While the ED50 of BAY 57-1293 was similar in the rat and in the mouse, valacyclovir showed decreased activity in the rat (Fig. 4).” (opens the source at this quote in a new tab)
“Treatment with 2 mg of BAY 57-1293 per kg t.i.d. is significantly better than treatment with 45 mg of valacyclovir per kg t.i.d.” (opens the source at this quote in a new tab)
“For both BAY 57-1293 and valacyclovir, the ED50s increased by approximately a factor of 6 with the once-daily dosing regimen compared to that with the t.i.d. dosing regimen.” (opens the source at this quote in a new tab)
“BAY 57-1293 continued to demonstrate efficacy when the onset of treatment was initiated after symptoms of herpetic disease were already apparent.” (opens the source at this quote in a new tab)

Potency relative to nucleoside analogues on a molar basis

“A comparison of the respective ED50 values from murine lethal challenge assays with acyclovir/valacyclovir/pritelivir (HSV-1, 22/17/0.5; HSV-2, 16/14/0.5)” (opens the source at this quote in a new tab)
“Using molar doses, which seem a more appropriate basis of comparison, the respective factors were 8- and 3-fold vs ganciclovir and 42- and 37-fold higher potencies of pritelivir relative to valacyclovir.” (opens the source at this quote in a new tab)

Murine encephalitis model: survival when treatment started 72 hours after infection

“Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 hours after infection for 7 days with pritelivir or acyclovir.” (opens the source at this quote in a new tab)
“When PTV was administered twice daily orally at doses of 30, 10, 3 or 1 mg/kg, survival was significantly increased to 80–100% as compared to the vehicle treatment (7%, P<0.0001) when therapy was initiated 72 h post viral inoculation.” (opens the source at this quote in a new tab)
“Even the lowest PTV dose of 0.3 mg/kg twice daily was effective in increasing survival to 53% (P=0.0015).” (opens the source at this quote in a new tab)
“With twice daily ACV treatment at 50 mg/kg, the positive control, survival was also significantly increased to 87% (P<0.0001).” (opens the source at this quote in a new tab)
“HSV-2 survival was significantly increased to 93–100% (P<0.0001) during PTV therapy when treatments of 30, 10 or 3 mg/kg twice daily were initiated 72 h post viral inoculation in comparison to the vehicle treated group with 13% survival.” (opens the source at this quote in a new tab)
“The 1 mg/kg twice daily dose of PTV also increased survival (73%) compared to the vehicle treated group (P=0.0005), but not the 0.3 mg/kg twice daily dose.” (opens the source at this quote in a new tab)

Murine encephalitis model: acyclovir-resistant HSV-1 and HSV-2 strains

“When PTV was orally administered twice daily at 3 or 1 mg/kg, survival was significantly increased (P<0.0001 and p=0.0025, respectively) when treatment was initiated 72 h post viral inoculation.” (opens the source at this quote in a new tab)
“Lower PTV doses and all ACV doses were ineffective in increasing survival as compared to the vehicle treatment with 7% survival.” (opens the source at this quote in a new tab)
“HSV-2 survival was significantly increased during PTV therapy when treatments of 3 or 1 mg/kg twice daily were initiated 72 h post viral inoculation in comparison to the vehicle treated group with 13% survival (P<0.0001).” (opens the source at this quote in a new tab)

Murine encephalitis model: combination with acyclovir

“ACV at the suboptimal dose of 10 mg/kg twice daily plus the suboptimal doses of PTV of 0.3 or 0.1 mg/kg twice daily showed improved survival to 47 or 40%, respectively, (P<0.0001) when compared to the vehicle treated group which had 0% survival.” (opens the source at this quote in a new tab)
“When compared to survival with ACV alone at 10 mg/kg twice daily (27%, not significant) or PTV alone at 0.3 or 0.1 mg/kg twice daily (7 or 13%, both not significant), a combination of both treatments seems to have a beneficial effect.” (opens the source at this quote in a new tab)
“The activity of PTV in the combination study with ACV indicates that there is at least an additive if not a synergistic effect against HSV-2, strain MS.” (opens the source at this quote in a new tab)

Murine encephalitis model: plasma and brain concentrations by dose

“Twice daily doses of 5 mg/kg, 15 mg/kg or 45 mg/kg resulted in mean plasma concentrations of 2 µg/ml, 4 µg/ml and 9 µg/ml, respectively, independent of infection status or time of initiation of dosing (Figure 5).” (opens the source at this quote in a new tab)
“Similarly, brain samples showed mean concentrations of approximately 0.05 µg/g for the 5 mg/kg dose group, 0.11 µg/g for the 15 mg/kg dose group and 0.22 µg/g for the mice given 45 mg/kg dose group independent of infection status or time of initiation of dosing (Figure 6).” (opens the source at this quote in a new tab)
“PTV was detected in the brain of both uninfected and infected animals and the brain exposure was proportional to the exposure in plasma.” (opens the source at this quote in a new tab)

Murine skin infection model: effective dose and exposure relative to the cell culture EC90

“The mean EC50 and EC90 values of pritelivir for the SC16 cl-2 strain were 0.01 μM and 0.03 μM, respectively (means derived from 3 independent experiments), and those for the cl-2-r1-Rec strain were 0.39 μM and 0.81 μM, respectively (means derived from 3 independent experiments).” (opens the source at this quote in a new tab)
“Taking into account both clinical signs and virus titers in the tissues, the 50% effective dose (ED50) was estimated to be between 1 and 5 mg/kg/day, whereas 10 mg/kg/day was able to completely suppress HSV-1 replication in infected animals without any visible lesions.” (opens the source at this quote in a new tab)
“Taking into account the fraction of pritelivir in murine plasma that is not bound to plasma proteins (0.8%, as obtained from equilibrium dialysis experiments; data not shown), the maximum plasma concentration (Cmax) and the plasma concentration 24 h after dosing (C24h) correspond to unbound concentrations of 141 ng/ml and 9 ng/ml, respectively.” (opens the source at this quote in a new tab)
“Therefore, pritelivir plasma concentrations were maintained above the unbound EC90 of 12 ng/ml for almost the entire dosing interval.” (opens the source at this quote in a new tab)

Murine skin infection model: treatment of a pritelivir-resistant mutant with a higher dose

“Hence, the mutant strain cl-2-r1-Rec showed a 27-fold decrease in sensitivity with regard to EC90, confirming the previously described resistance phenotype” (opens the source at this quote in a new tab)
“Therapy using 5 mg/kg, exceeding the ED50 for the wild-type virus, had no significant impact on clinical signs or virus titers for the pritelivir-resistant mutant cl-2-r1-Rec (Fig. 3).” (opens the source at this quote in a new tab)
“Interestingly, by increasing the dose 6-fold and prolonging the treatment duration to 8 days, it was possible to treat mice infected with an approximately 30-fold pritelivir-resistant but fully pathogenic HSV-1 virus.” (opens the source at this quote in a new tab)
“As shown in Fig. 5, the plasma concentration in mice after a single dose of 60 mg/kg exceeded the cell culture EC50 for HSV-1 mutant cl-2-r1-Rec for approximately 20 h, but the EC90 was exceeded for only approximately 10 h.” (opens the source at this quote in a new tab)
“Corresponding plasma concentrations exceeded the EC90 of this mutant for <8 h, indicating that even suboptimal exposure to pritelivir is sufficient to achieve antiviral efficacy, possibly augmented by other factors such as the immune system.” (opens the source at this quote in a new tab)

Translation of the murine exposure target to the phase 2 dose range

“Correction for protein binding in human plasma (fu = 2.8%, determined by equilibrium analysis) resulted in an unbound mean Cmax of 38.0 ng/ml and an unbound Ctrough of 23.3 ng/ml, exceeding the EC90 for HSV-1 of 12 ng/ml derived from cell cultures.” (opens the source at this quote in a new tab)
“Based on the good nonclinical PK-PD correlation, a dose of 75 mg per day was selected as the highest daily dose in a phase 2 proof-of-concept and dose-finding trial in HSV-2-positive persons with genital herpes” (opens the source at this quote in a new tab)
“Besides the PK-PD data, this dose selection took into account variability in plasma exposures among individuals, as well as variability in susceptibility among clinical isolates and between HSV 1 and 2” (opens the source at this quote in a new tab)

Murine skin infection model: mixtures of wild-type and resistant virus

“The employed mutant commanded an in vitro EC50 of >248 μmol/L compared to a wild-type EC50 of 0.03 μmol/L.” (opens the source at this quote in a new tab)
“Wild-type, mutant/wild-type mixtures of 1:50 and 1:500, and mutant alone were studied in groups of 5–6 mice.” (opens the source at this quote in a new tab)
“The respective mortalities at 8 days without active treatment were 100, 100, 80, and 60%, respectively.” (opens the source at this quote in a new tab)
“Oral treatment with 5 mg/kg pritelivir from day 1 to day 4 postinfection caused the expected favorable responses in the wild type and the two mixture groups (except for some small lesions in 1/5 mice of each group), whereas infection with the HSV-1 mutant without wild-type mixture rendered the drug practically ineffective, even at the high dose of 60 mg/kg.” (opens the source at this quote in a new tab)
“Values fell below the detection limit in skin samples and ear pinna derived from the 1:500 mutant/wild-type mixture group.” (opens the source at this quote in a new tab)

Immunocompetent and immunodeficient mice: virus titers after short treatment courses

“As anticipated, all these effects were prevented by pritelivir in immunocompetent animals (15 mg/kg, administered orally or intraperitoneally once daily on days 1–4 postinfection; 5 mice per group).” (opens the source at this quote in a new tab)
“Viral titers were reduced below the level of detection after 2 days of treatment (skin) or replication was prevented entirely (ear pinna and brainstem).” (opens the source at this quote in a new tab)
“Immunodeficient mice were studied in group sizes of 2 animals.” (opens the source at this quote in a new tab)
“Pritelivir was administered in single doses by intraperitoneal injection at 1.5 or 15 mg/kg on postinfection day 3 or on days 3 and 4.” (opens the source at this quote in a new tab)
“The more extensive treatment (higher dose, 2 days) caused impressive reductions of the virus yield at the inoculation and secondary sites (ear and brainstem).” (opens the source at this quote in a new tab)
“Experiments in a small number of immunodeficient mice (cf. section 2.2.1) suggest that there is no fast development of resistance to pritelivir in this setting.” (opens the source at this quote in a new tab)

Guinea pig model of genital herpes: shedding, lesion score, and recurrence

“Pritelivir caused the expected drop of the lesion score not only when given as early treatment but also when therapy was commenced with a delay (Figure 9).” (opens the source at this quote in a new tab)
“On day 2 postinfection, shedding decreased by 3 orders of magnitude in the pritelivir group compared to controls (20 mg/kg b.i.d.).” (opens the source at this quote in a new tab)
“In contrast, there was no discernible effect from valacyclovir.” (opens the source at this quote in a new tab)
“Rates for pritelivir (20 and 30 mg/kg, b.i.d.) were 0.4 and 0.3, respectively, marking statistically significant difference vs valacyclovir (0.9; 100 mg/kg t.i.d. or 150 mg/kg, b.i.d.) which was very similar to the control (1.0).” (opens the source at this quote in a new tab)
“Oral treatment with pritelivir (20 mg/kg b.i.d., administered from day 4 to day 14 postinfection) halved the time to return to a disease score of zero from 14 to 7 days (n = 10 per group).” (opens the source at this quote in a new tab)
“Valacyclovir (150 mg/kg b.i.d.) decreased the time by only 2 days (12 vs 14 days).” (opens the source at this quote in a new tab)
“To date, there is no convincing clinical evidence yet that helicase–primase inhibitors have an impact on viral latency.” (opens the source at this quote in a new tab)

Ocular HSV-1 models: reactivation in mice and keratitis in rabbits

“Oral BAY 57-1293 suppressed reactivation in HSV-1-infected mice and reduced the viral load in TG up to four orders of magnitude.” (opens the source at this quote in a new tab)
“In an additional heat-stressed mouse study, orally administered BAY 57-1293 reduced the presence of herpes virus in the tears statistically significantly (P = 0.0061; exact chi-square test) more effectively than vehicle alone (Table 1).” (opens the source at this quote in a new tab)
“In the first oral dosage study, once-daily oral treatment with 500 mg/kg BAY 57-1293 was as effective as twice-a-day topical treatment with trifluridine (Fig. 3A), with no statistically significant differences seen in the severity of keratitis on PI days 4, 5, or 6 (P = 1.000 all times).” (opens the source at this quote in a new tab)
“Keratitis in the animals treated with 40 mg/kg/day BAY-1293 was significantly less severe, compared with the animals treated with valacyclovir alone (P = 0.0116, < 0.0001, < 0.0001, and < 0.0001, on PI days 4, 5, 6, and 7, respectively).” (opens the source at this quote in a new tab)

Combined antiviral activity with acyclovir or foscarnet in cell culture

“The average δ score, calculated for the entire dose–response matrix, revealed additive effects for the ACV + PTV (6.624 ± 10.6) and PFA + PTV (4.395 ± 6) combinations, whereas δ scores calculated for the most synergistic 3-by-3 dose region in the dose–response matrix (Fig. 1, black box) implied synergy for both ACV and PTV (13.54) and PFA and PTV (12.14).” (opens the source at this quote in a new tab)
“Our data suggest that combining the helicase–primase inhibitor PTV with a DP inhibitor may be an effective strategy to prevent drug resistance evolution in HSV-1.” (opens the source at this quote in a new tab)