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Holger Zimmermann - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and safety of Letermovir coadministered with cyclosporine a or tacrolimus in healthy subjects
Clinical pharmacology in drug development, 2018Co-Authors: Dirk Kropeit, Oliver Von Richter, Hanspeter Stobernack, Helga Rubsamenschaeff, Holger ZimmermannAbstract:: Letermovir is being developed for human cytomegalovirus infection treatment and prophylaxis. In patients receiving transplants, antivirals are coadministered with cyclosporine A (CsA) or tacrolimus (TAC) immunosuppressants. Therefore, we investigated the potential for Letermovir-immunosuppressant interactions. In 2 phase 1 clinical trials either CsA 50 mg or TAC 5 mg was administered to healthy males. Following washout, Letermovir 80 mg was dosed twice daily for 7 and 11 days in the CsA and TAC trials, respectively, with a second dose of immunosuppressant coadministered with Letermovir at steady state. In addition, Letermovir 40 mg twice daily was administered for 14 days, and either CsA 50 or 200 mg administered on days 7 and 14. Pharmacokinetics and tolerability were assessed. Letermovir increased CsA and TAC Cmax by 37% and 70%, respectively, and exposure by 70% and 78%, respectively, compared with immunosuppressant alone; t½ was also increased from 10.7 to 17.9 hours for CsA. CsA (50/200 mg) increased Letermovir Cmax,ss (109%/167%) and AUCss,τ (126%/237%) and decreased t½ (4.33 to 3.68/3.04 hours) versus Letermovir alone. TAC did not significantly affect Letermovir pharmacokinetics. All treatments were well tolerated. Concomitant Letermovir increased TAC and CsA exposure. CsA altered Letermovir pharmacokinetics, whereas TAC did not.
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pharmacokinetics and safety of the anti human cytomegalovirus drug Letermovir in subjects with hepatic impairment
British Journal of Clinical Pharmacology, 2017Co-Authors: Dirk Kropeit, Hanspeter Stobernack, Holger Zimmermann, David Mccormick, Katharina Erbzohar, Valentin S Moiseev, Z Kobalava, Helga RubsamenschaeffAbstract:Aims Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged Letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on Letermovir pharmacokinetics. Methods Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral Letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg Letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg Letermovir/day. Pharmacokinetic parameters were determined from blood samples. Results For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss) for total Letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total Letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. Conclusions Moderate hepatic impairment increased exposure to Letermovir <2-fold, while severe hepatic impairment increased Letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.
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pharmacokinetics and safety of Letermovir a novel anti human cytomegalovirus drug in patients with renal impairment
British Journal of Clinical Pharmacology, 2017Co-Authors: Dirk Kropeit, Hanspeter Stobernack, Holger Zimmermann, Katharina Erbzohar, Arne Van Schanke, Jurgen Scheuenpflug, Atef Halabi, Ellen G J Hulskotte, Helga RubsamenschaeffAbstract:AIMS: Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, Letermovir, is in development. We assessed Letermovir pharmacokinetics in renal impairment. METHODS: This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min-1 1.73m-2 ), moderate (30-59 ml min-1 1.73m-2 ) and severe (<30 ml min-1 1.73m-2 ) impairment. Oral Letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. RESULTS: All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound Letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total Letermovir vs. healthy subjects, AUCτ,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound Letermovir concentration (R2 = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2 = 0.0662, P = 0.2249 and R2 = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2 = 0.3548, P = 0.0021 and R2 = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose Letermovir 120 mg was well tolerated across groups. CONCLUSIONS: Renal impairment increased exposure to Letermovir, although age was a confounding factor.
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Pharmacokinetics and safety of the anti-human cytomegalovirus drug Letermovir in subjects with hepatic impairment.
British Journal of Clinical Pharmacology, 2017Co-Authors: Dirk Kropeit, Holger Zimmermann, David Mccormick, Valentin S Moiseev, Z Kobalava, Katharina Erb‐zohar, Hans‐peter Stobernack, Helga Rübsamen‐schaeffAbstract:Aims Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged Letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on Letermovir pharmacokinetics. Methods Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral Letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg Letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg Letermovir/day. Pharmacokinetic parameters were determined from blood samples. Results For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss) for total Letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total Letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. Conclusions Moderate hepatic impairment increased exposure to Letermovir
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intravenous hydroxypropyl β cyclodextrin formulation of Letermovir a phase i randomized single ascending and multiple dose trial
Clinical and Translational Science, 2017Co-Authors: Katharina Erbzohar, Dirk Kropeit, Holger Zimmermann, J Scheuenpflug, Hp Stobernack, Egj Hulskotte, A Van Schanke, Helga RubsamenschaeffAbstract:Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β-cyclodextrin (HPβCD)-based intravenous formulation of Letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 Letermovir, 2 placebo per cohort) or multiple, once-daily doses (240 mg; 8 Letermovir, 4 placebo) of HPβCD-formulated Letermovir and the associated pharmacokinetic profiles and adverse events were investigated. Single-dose and multiple-dose regimens were generally well tolerated. Single-dose escalation resulted in a slightly more-than-dose-proportional increase in the area under the Letermovir plasma concentration–time curve (AUC), whereas increase in the maximal observed Letermovir plasma concentration (Cmax) was dose proportional. After once-daily dosing, accumulation ratios in AUC and Cmax were 1.22 and 1.03, respectively. The terminal half-life was 28.3 h, supporting once-daily dosing (EudraCT Number: 2012-001603-20).
Peter Lischka - One of the best experts on this subject based on the ideXlab platform.
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impact of glycoprotein b genotype and naturally occurring orf ul56 polymorphisms upon susceptibility of clinical human cytomegalovirus isolates to Letermovir
Antiviral Research, 2016Co-Authors: Peter Lischka, Douglas Zhang, Daniel J Holder, Holger ZimmermannAbstract:Abstract Letermovir is a novel anti-HCMV drug in Phase III development that targets the UL56 subunit of the viral terminase complex. In immunocompromised patients four major glycoprotein B (gB) subtypes are known and may influence pathogenesis and thus disease outcomes. Using a panel of 74 Letermovir-naive, low-passage, clinical HCMV isolates, we examined the potential impact of i) gB genotype and ii) naturally occurring UL56 sequence variations upon susceptibility to Letermovir. Our data show that Letermovir’s potency is independent of gB subtype and show that naturally-occurring Letermovir-resistance is rare or possibly absent.
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characterization of cytomegalovirus breakthrough events in a phase 2 prophylaxis trial of Letermovir aic246 mk 8228
The Journal of Infectious Diseases, 2016Co-Authors: Peter Lischka, Detlef Michel, Holger ZimmermannAbstract:BACKGROUND: The efficacy of different Letermovir (AIC246, MK8228) doses (60, 120, and 240 mg/day) against human cytomegalovirus (HCMV) was evaluated in a recent phase 2b dose-range-finding prophylaxis study in stem-cell transplant recipients. Here we report the genotypic and phenotypic characterization of 15 viral breakthroughs considered to be virological failures. METHODS: Direct sequencing of an HCMV open reading frame UL56 region that included amino acids 230-370 and thus encompassed all known Letermovir resistance mutations was followed by marker-transfer experiments to assess the impact of the identified sequence polymorphisms on viral fitness and susceptibility to Letermovir. RESULTS: UL56 genotyping was successful for 12 of 15 patients. Six amino acid substitutions were detected in 5 patients. In 1 subject from the 60-mg-dose group, the known Letermovir resistance mutation V236M was identified subsequent to a wild-type viremic episode. The remaining 5 sequence variants (L134V, S227I, Q228H, R410G, and D414N) were shown to be inert with regard to Letermovir susceptibility, thus representing natural polymorphisms. CONCLUSIONS: Our findings represent the first case of a Letermovir resistance mutation emerging in the clinic, apparently because of a suboptimal prophylactic dose (60 mg/day). This is in agreement with the trial's efficacy analyses, findings of which suggest that Letermovir doses of 60 mg/day and 120 mg/day are suboptimal for prophylaxis whereas a dose of 240 mg/day appears to achieve complete suppression of viremia.
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in vitro drug combination studies of Letermovir aic246 mk 8228 with approved anti human cytomegalovirus hcmv and anti hiv compounds in inhibition of hcmv and hiv replication
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Steffen Wildum, Holger Zimmermann, Peter LischkaAbstract:Despite modern prevention and treatment strategies, human cytomegalovirus (HCMV) remains a common opportunistic pathogen associated with serious morbidity and mortality in immunocompromised individuals, such as transplant recipients and AIDS patients. All drugs currently licensed for the treatment of HCMV infection target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Letermovir (AIC246, MK-8228) is a new anti-HCMV agent in clinical development that acts via a novel mode of action and has demonstrated anti-HCMV activity in vitro and in vivo. For the future, drug combination therapies, including Letermovir, might be indicated under special medical conditions, such as the emergence of multidrug-resistant virus strains in transplant recipients or in HCMV-HIV-coinfected patients. Accordingly, knowledge of the compatibility of Letermovir with other HCMV or HIV antivirals is of medical importance. Here, we evaluated the inhibition of HCMV replication by Letermovir in combination with all currently approved HCMV antivirals using cell culture checkerboard assays. In addition, the effects of Letermovir on the antiviral activities of selected HIV drugs, and vice versa, were analyzed. Using two different mathematical techniques to analyze the experimental data, (i) additive effects were observed for the combination of Letermovir with anti-HCMV drugs and (ii) no interaction was found between Letermovir and anti-HIV drugs. Since none of the tested drug combinations significantly antagonized Letermovir efficacy (or vice versa), our findings suggest that Letermovir may offer the potential for combination therapy with the tested HCMV and HIV drugs.
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phenotypic characterization of two naturally occurring human cytomegalovirus sequence polymorphisms located in a distinct region of orf ul56 known to be involved in in vitro resistance to Letermovir
Antiviral Research, 2015Co-Authors: Thomas Goldner, Holger Zimmermann, Peter LischkaAbstract:Letermovir is a new drug in Phase 3 clinical development for the prevention of human Cytomegalovirus (HCMV) infections in hematopoietic-stem-cell transplant recipients (HSCT). In contrast to marketed anti-HCMV drugs which all target the viral DNA polymerase, Letermovir’s novel mode of action targets the UL56 subunit of the viral terminase complex. Consistently Letermovir resistance has mapped in vitro to a distinct region within ORF UL56 (amino acid 230–370). Here we used marker transfer to demonstrate that two naturally occurring UL56 sequence variants within this region, located directly adjacent to sites known to mediate Letermovir resistance in vitro (D242G and A327V) represent normal interstrain polymorphisms unrelated to drug-resistance.
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geno and phenotypic characterization of human cytomegalovirus mutants selected in vitro after Letermovir aic246 exposure
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Thomas Goldner, Holger Zimmermann, Christine Hempel, Helga Ruebsamenschaeff, Peter LischkaAbstract:Letermovir is a novel antiviral compound currently in clinical development for the prevention of human cytomegalovirus (HCMV) infections. In contrast to all currently approved anti-HCMV drugs that target the viral DNA polymerase, Letermovir acts via a distinct mode of action involving the viral terminase subunit pUL56. To extend our understanding of potential Letermovir resistance mechanisms, we used marker transfer to characterize mutations identified in Letermovir-resistant HCMV variants that were selected in cell culture.
Sunwen Chou - One of the best experts on this subject based on the ideXlab platform.
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Advances in the genotypic diagnosis of cytomegalovirus antiviral drug resistance.
Antiviral Research, 2020Co-Authors: Sunwen ChouAbstract:Abstract Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor Letermovir and the UL97 kinase inhibitor maribavir. Newly mapped mutations and their phenotypes provide more detail on cross-resistance properties and suggest the need to expand the CMV gene regions covered in diagnostic testing. Next-generation deep sequencing technology offers a more sensitive, higher resolution view of emerging antiviral resistance and is recommended for use in clinical trials. Issues of standardization and diagnostic utility in comparison with traditional Sanger sequencing remain unresolved. Quality control is important for the accurate and reproducible detection of mutant viral populations in clinical specimens.
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emergence of Letermovir resistance in a lung transplant recipient with ganciclovir resistant cytomegalovirus infection
American Journal of Transplantation, 2018Co-Authors: Lauren Cherrier, Aasya Nasar, Kellie J Goodlet, Michael D Nailor, Sofya Tokman, Sunwen ChouAbstract:: Following a year of valganciclovir prophylaxis, a lung transplant recipient developed cytomegalovirus (CMV) infection that became resistant to ganciclovir, as confirmed by detection of UL97 kinase mutation M460V and a previously uncharacterized UL54 DNA polymerase mutation L516P. The latter mutation is now shown to confer ganciclovir and cidofovir resistance. As predicted from the viral genotype, foscarnet therapy was effective, but resumption of valganciclovir as secondary prophylaxis resulted in a plasma viral load rebound to 3.6 log10 copies/mL several weeks later. Valganciclovir was then replaced by Letermovir, resulting in gradual viral load reduction in the first 5 weeks to below the quantitation limit (2.7 log10 copies/mL) for 1 week, followed by 10 weeks of rising viral loads reaching 4.3 log10 copies/mL while on Letermovir. At this point, CMV genotypic testing revealed UL56 mutation C325Y, which confers absolute resistance to Letermovir. Retreatment with foscarnet was successful. This case adds to the considerable list of proven ganciclovir resistance mutations, and provides an early experience with Letermovir resistance after off-label therapeutic use. This experience is consistent with in vitro observations of rapid emergence of Letermovir-resistant CMV after drug exposure.
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new locus of drug resistance in the human cytomegalovirus ul56 gene revealed by in vitro exposure to Letermovir and ganciclovir
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Sunwen Chou, Elizabeth L Satterwhite, Ronald J ErcolaniAbstract:: Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of Letermovir and ganciclovir. In eight experiments, UL56 terminase gene mutations were detected beginning at 10 passages and included novel amino acid substitutions V236A, L328V, and A365S in a region previously associated with Letermovir resistance. Outside this region, the UL56 substitution C25F was detected at moderate drug concentrations in two experiments as either the first detected mutation or an addition to a preexisting V231L substitution. In all cases, mutation at UL56 codon 325 conferring absolute Letermovir resistance eventually developed at a median of 20 passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to ganciclovir resistance were detected until many passages after the first detection of the UL56 mutations. UL56 substitutions V236A, L328V, and A365S were shown to confer borderline or low-grade Letermovir resistance, while C25F conferred a 5.4-fold increase in Letermovir resistance (50% effective concentration [EC50]) by itself and a 46-fold increase in combination with V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97 is consistent with prior in vitro observations, and UL56 codon 25 is a genetic locus for Letermovir resistance distinct from loci previously described.
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Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus.
Antiviral Research, 2018Co-Authors: Sunwen Chou, Ronald J Ercolani, Katayoun DerakhchanAbstract:Abstract The human cytomegalovirus (CMV) UL97 kinase inhibitor maribavir is in Phase III clinical trials as antiviral therapy, including use for infections refractory or resistant to standard therapy. To assess its activity in combination with approved and experimental CMV antivirals, and with the mTor inhibitor rapamycin (sirolimus), drug effects were tested by in vitro checkerboard assays and the data were analyzed using a three dimensional model based on an independent effects definition of additive interactions. Baseline virus and representative drug-resistant mutants were tested. According to the volume of synergy at 95% confidence, maribavir showed additive interactions with foscarnet, cidofovir, Letermovir and GW275175X when tested against wild type and mutant viruses, strong antagonism with ganciclovir, and strong synergy with rapamycin, the latter suggesting a potentially useful therapeutic combination.
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a third component of the human cytomegalovirus terminase complex is involved in Letermovir resistance
Antiviral Research, 2017Co-Authors: Sunwen ChouAbstract:Abstract Letermovir is a human cytomegalovirus (CMV) terminase inhibitor that was clinically effective in a Phase III prevention trial. In vitro studies have shown that viral mutations conferring Letermovir resistance map primarily to the UL56 component of the terminase complex and uncommonly to UL89. After serial culture of a baseline CMV laboratory strain under Letermovir, mutation was observed in a third terminase component in 2 experiments, both resulting in amino acid substitution P91S in gene UL51 and adding to a pre-existing UL56 mutation. Recombinant phenotyping indicated that P91S alone conferred 2.1-fold increased Letermovir resistance (EC50) over baseline, and when combined with UL56 mutation S229F or R369M, multiplied the level of resistance conferred by those mutations by 3.5–7.7-fold. Similarly a combination of UL56 mutations S229F, L254F and L257I selected in the same experiment conferred 54-fold increased Letermovir EC50 over baseline, but 290-fold when combined with UL51 P91S. The P91S mutant was not perceptibly growth impaired. Although pUL51 is essential for normal function of the terminase complex, its biological significance is not well understood. Letermovir resistance mutations mapping to 3 separate genes, and their multiplier effect on the level of resistance, suggest that the terminase components interactively contribute to the structure of a Letermovir antiviral target. The diagnostic importance of the UL51 P91S mutation arises from its potential to augment the Letermovir resistance of some UL56 mutations at low fitness cost.
Helga Rubsamenschaeff - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and safety of Letermovir coadministered with cyclosporine a or tacrolimus in healthy subjects
Clinical pharmacology in drug development, 2018Co-Authors: Dirk Kropeit, Oliver Von Richter, Hanspeter Stobernack, Helga Rubsamenschaeff, Holger ZimmermannAbstract:: Letermovir is being developed for human cytomegalovirus infection treatment and prophylaxis. In patients receiving transplants, antivirals are coadministered with cyclosporine A (CsA) or tacrolimus (TAC) immunosuppressants. Therefore, we investigated the potential for Letermovir-immunosuppressant interactions. In 2 phase 1 clinical trials either CsA 50 mg or TAC 5 mg was administered to healthy males. Following washout, Letermovir 80 mg was dosed twice daily for 7 and 11 days in the CsA and TAC trials, respectively, with a second dose of immunosuppressant coadministered with Letermovir at steady state. In addition, Letermovir 40 mg twice daily was administered for 14 days, and either CsA 50 or 200 mg administered on days 7 and 14. Pharmacokinetics and tolerability were assessed. Letermovir increased CsA and TAC Cmax by 37% and 70%, respectively, and exposure by 70% and 78%, respectively, compared with immunosuppressant alone; t½ was also increased from 10.7 to 17.9 hours for CsA. CsA (50/200 mg) increased Letermovir Cmax,ss (109%/167%) and AUCss,τ (126%/237%) and decreased t½ (4.33 to 3.68/3.04 hours) versus Letermovir alone. TAC did not significantly affect Letermovir pharmacokinetics. All treatments were well tolerated. Concomitant Letermovir increased TAC and CsA exposure. CsA altered Letermovir pharmacokinetics, whereas TAC did not.
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pharmacokinetics and safety of the anti human cytomegalovirus drug Letermovir in subjects with hepatic impairment
British Journal of Clinical Pharmacology, 2017Co-Authors: Dirk Kropeit, Hanspeter Stobernack, Holger Zimmermann, David Mccormick, Katharina Erbzohar, Valentin S Moiseev, Z Kobalava, Helga RubsamenschaeffAbstract:Aims Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged Letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on Letermovir pharmacokinetics. Methods Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral Letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg Letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg Letermovir/day. Pharmacokinetic parameters were determined from blood samples. Results For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss) for total Letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total Letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. Conclusions Moderate hepatic impairment increased exposure to Letermovir <2-fold, while severe hepatic impairment increased Letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.
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pharmacokinetics and safety of Letermovir a novel anti human cytomegalovirus drug in patients with renal impairment
British Journal of Clinical Pharmacology, 2017Co-Authors: Dirk Kropeit, Hanspeter Stobernack, Holger Zimmermann, Katharina Erbzohar, Arne Van Schanke, Jurgen Scheuenpflug, Atef Halabi, Ellen G J Hulskotte, Helga RubsamenschaeffAbstract:AIMS: Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, Letermovir, is in development. We assessed Letermovir pharmacokinetics in renal impairment. METHODS: This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min-1 1.73m-2 ), moderate (30-59 ml min-1 1.73m-2 ) and severe (<30 ml min-1 1.73m-2 ) impairment. Oral Letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. RESULTS: All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound Letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total Letermovir vs. healthy subjects, AUCτ,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound Letermovir concentration (R2 = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2 = 0.0662, P = 0.2249 and R2 = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2 = 0.3548, P = 0.0021 and R2 = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose Letermovir 120 mg was well tolerated across groups. CONCLUSIONS: Renal impairment increased exposure to Letermovir, although age was a confounding factor.
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intravenous hydroxypropyl β cyclodextrin formulation of Letermovir a phase i randomized single ascending and multiple dose trial
Clinical and Translational Science, 2017Co-Authors: Katharina Erbzohar, Dirk Kropeit, Holger Zimmermann, J Scheuenpflug, Hp Stobernack, Egj Hulskotte, A Van Schanke, Helga RubsamenschaeffAbstract:Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β-cyclodextrin (HPβCD)-based intravenous formulation of Letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 Letermovir, 2 placebo per cohort) or multiple, once-daily doses (240 mg; 8 Letermovir, 4 placebo) of HPβCD-formulated Letermovir and the associated pharmacokinetic profiles and adverse events were investigated. Single-dose and multiple-dose regimens were generally well tolerated. Single-dose escalation resulted in a slightly more-than-dose-proportional increase in the area under the Letermovir plasma concentration–time curve (AUC), whereas increase in the maximal observed Letermovir plasma concentration (Cmax) was dose proportional. After once-daily dosing, accumulation ratios in AUC and Cmax were 1.22 and 1.03, respectively. The terminal half-life was 28.3 h, supporting once-daily dosing (EudraCT Number: 2012-001603-20).
Brian C Shaffer - One of the best experts on this subject based on the ideXlab platform.
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Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients real world experience
Transplant Infectious Disease, 2019Co-Authors: Molly Maloy, Yiqi Su, Valkal Bhatt, Lauren Derespiris, Meagan Griffin, Anthony J Proli, Juliet N Barker, Brian C ShafferAbstract:: Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) patients. We evaluated the efficacy of Letermovir as primary and secondary prophylaxis in 53 CMV-seropositive hematopoietic stem cell transplant recipients. 70% of patients were at high risk for CMV reactivation and disease (primarily ex vivo T-cell-depleted HCT [n = 18; 34%] or haploidentical T-replete HCT [n = 12; 23%]). This was a retrospective, single-center study which identified patients transplanted between January 2018 and June 2018. Patients were followed through September 2018. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Primary Letermovir prophylaxis started at a median of 7 days (range, 7-40) after allo-HCT. The median duration of primary Letermovir prophylaxis was 116 days (range, 12-221). With primary prophylaxis in 39 patients, the observed CMV reactivation rate was 5.1%. Twenty-nine patients continued primary prophylaxis beyond 14 weeks with a reactivation rate of 3.4%. No recurrent reactivation was seen with secondary prophylaxis of an additional 14 patients. Our experience demonstrates the efficacy of Letermovir in a real-world setting for CMV prevention for the first 14 weeks and continued efficacy when given longer than 14 weeks after allogeneic stem cell transplantation or as secondary prophylaxis.
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Letermovir in allogeneic hematopoietic cell transplantation beyond the label
Biology of Blood and Marrow Transplantation, 2019Co-Authors: Molly Maloy, Valkal Bhatt, Lauren Derespiris, Meagan Griffin, Anthony J Proli, Juliet N Barker, Brian C Shaffer, Sergio Giralt, Ann A Jakubowski, Esperanza B PapadopoulosAbstract:Background Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (allo-HCT) patients (pts). Cumulative incidence of CMV infection in high-risk patients such as CD34-selected or haploidentical HCT have been reported as high as 61.8-84.5% and 53-81%, respectively. Letermovir (LTV) was approved in 11/2017 for prophylaxis (ppx) in CMV-seropositive recipients (R+) of allo-HCT. Since 12/2017, LTV ppx was implemented at our center for both primary and secondary ppx. We report our real-world experience. Methods Adult CMV R+ allo-HCT pts who initiated LTV as primary or secondary prophylaxis were identified between 1/1/2018 and 6/30/18. Cord blood transplants were excluded. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Pts were followed through 9/2018. Results 53 pts initiated LTV. 69.8% pts were at high risk for CMV reactivation and disease (primarily ex vivo T-cell depleted HCT [n = 18; 34%] or haploidentical T-replete HCT [n = 12; 22.6%]). Baseline characteristics are summarized in Table 1. 39 pts (73.5%) received LTV as primary ppx after HCT, with a median day of LTV initiation of D+7 (range D+7 D+40). At LTV initiation, 34 pts had an undetectable CMV DNA, and 4 had CMV Conclusion Primary LTV ppx significantly reduced CMV reactivation, and high-risk patients may benefit from extended prophylaxis. In patients who received preemptive therapy for CMV, use of secondary ppx showed no recurrent CMV reactivation. LTV is well tolerated. Additional studies are needed to determine optimal ppx duration and to clarify role of secondary CMV ppx in high-risk allo-HCT. The future standard of care will likely include extended primary ppx and secondary ppx and result in decreased morbidity and mortality associated with CMV.