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Ombitasvir (trade name; Viekira Pak; formerly known as ABT-267) is a novel and potent hepatitis C virus (HCV) NS5A inhibitor based on N-phenylpyrrolidines that exhibits good pharmacokinetics/PK, metabolic stability, and potency. Ombitasvir was discovered to be a pan-genotypic HCV inhibitor, with an EC50 range of 366 pM against GT6a and 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a. In treatment-naive HCV GT1-infected subjects, it reduced HCV RNA up to 3.10 log10 IU/mL during a 3-day monotherapy. Under the brand name Viekira Pak, ombitasvir has received FDA approval for use in combination with paritaprevir, ritonavir, and dasabuvir as antiviral medications.
| Targets |
HCV (IC50 = 0.82 to 19.3 pM); HCV (IC50 = 366 pM)
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| ln Vitro |
Ombitasvir (ABT-267) is a picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a hepatitis C virus (HCV) NS5A inhibitor. When it comes to genotype 1a-H77 and genotype 1b-Con1 subgenomic replicons, ombitasvir's EC50 values are 14.1 and 5.0 pM, respectively[1].
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| ln Vivo |
Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.)[1].
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| Enzyme Assay |
The techniques previously described were used to quantify how different amino acid variants affected an inhibitor's activity in HCV replicon cell culture assays. In short, using the Change-IT multiple-mutation site-directed mutagenesis kit (Affymetrix, Santa Clara, CA), the resistance-associated variants in NS5A were each introduced into the genotype 1a-H77 or 1b-Con1 or one of the chimeric genotype 2 to 6 replicons. After sequence analysis verified the variant's existence, the plasmid was linearized and the HCV subgenomic RNA was extracted using the TranscriptAid T7 high-yield transcription kit (Fermentas, Glen Burnie, MD). Through electroporation, a Huh-7 cell line was transfected with the variant-containing replicon RNA in a temporary experiment. As mentioned in the earlier sections, the EC50s were computed.
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| Cell Assay |
A genotype 1b-Con1 HCV replicon-based shuttle vector cassette lacking the Neo gene but containing a luciferase reporter was created to evaluate the NS5A gene phenotypes in patients infected with HCV genotypes 1 through 6. 90 nucleotides upstream of NS5A in the 3′ end of NS4B, a NotI restriction site was cloned into the 1b-Con1 subgenomic replicon vector, and a ClaI site was cloned after the NS5A amino acid 413 codon. The NotI and ClaI restriction sites were crossed with the NS5A region from patients with genotype 1 infection. Ombitasvir's ability to inhibit the NS5A region of non-genotype 1 HCV, which contains amino acids 1 through 214, was assessed using the 1b-Con1 shuttle vector with NotI and BlpI restriction sites (discussed in the preceding section). An amplified copy of the NS5A gene was ligated into the shuttle vector using clinical samples. One transient assay involved electroporating each clinical sample's HCV subgenomic replicon RNA containing the NS5A gene into a cell line derived from Huh-7. Ombitasvir was present during the four days that the cells were cultured. Following the procedure previously mentioned, the luciferase activity in the cells was determined.
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| Animal Protocol |
Clinical study design. Study M12-116 (ClinicalTrials.gov registration no. NCT01181427) was the first study to evaluate the pharmacokinetics, safety, tolerability, antiviral activity, and resistance of ombitasvir in HCV-infected treatment-naive adults. All of the patients provided written informed consent. The study was performed in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki, and the study protocol was approved by the relevant institutional review boards and regulatory agencies. Inclusion criteria included chronic HCV genotype 1 infection for at least 6 months prior to study enrollment, plasma HCV RNA level of >100,000 IU/ml at screening, and a liver biopsy within the past 3 years with histology consistent with HCV-related inflammation and fibrosis but no evidence of cirrhosis. Exclusion criteria included positive antibodies for hepatitis A or B virus or human immunodeficiency virus type 1 (HIV-1) or a history of clinically significant comorbidities. The primary endpoint was the maximum change from baseline in HCV RNA. The patients in the ombitasvir dose groups were enrolled sequentially, and within each group, patients were randomized (2:1) to either ombitasvir or placebo and treated under nonfasting conditions for 3 days while confined to the study site. The 200-mg dose group received a different formulation with higher bioavailability. Patients who received at least one dose of ombitasvir or placebo were provided the option to receive treatment with pegIFN/RBV for approximately 48 weeks once treatment with ombitasvir was completed. HCV RNA was measured using the Roche COBAS TaqMan HCV Test v2.0 real-time reverse transcriptase PCR assay (with a lower limit of quantification of 25 IU/ml and a lower limit of detection of 10 IU/ml). The virologic response was assessed as HCV RNA decrease from baseline in log10 IU/ml[1].
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Ombitasvir reaches peak plasma concentration 5 hours after administration. It has an absolute bioavailability of 48%. Taking ombitasvir with high or normal fat meals increases exposure by 1.76 or 1.82 fold respectively. Ombitasvir is mainly excreted in the feces (90.2%) with very little excreted in the urine (1.91%). 87.8% and 0.03% of the dose excreted in the feces and urine respectively is present as the parent compound. Ombitasvir has a volume of distribution at steady state of 173 liters. Clearance of Ombitasvir has not been determined. Metabolism / Metabolites Ombitasvir is mainly metabolized by amide hydrolysis followed by CYP2C8-mediated oxidative metabolism. Biological Half-Life Ombitasvir has a half life of elimination of 21-25 hours |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation Ombitasvir has not been studied in nursing mothers being treated for hepatitis C infection. Because it is 99.9% bound to maternal plasma proteins, amounts in breastmilk are likely to be very low. Some sources recommend against breastfeeding when ombitasvir is used with ribavirin. Ritonavir used as a booster has been studied in several studies of breastfeeding mothers. It is excreted into milk in measurable concentrations and low levels can be found in the blood of some breastfed infants. No reports of adverse reactions in breastfed infants have been reported. For more information, refer to the LactMed record on ritonavir. Hepatitis C is not transmitted through breastmilk and breastmilk has been shown to inactivate hepatitis C virus (HCV). However, the Centers for Disease Control recommends that mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. It is not clear if this warning would apply to mothers who are being treated for hepatitis C. Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Ombitasvir is 99.9% bound to human plasma proteins. |
| References | |
| Additional Infomation |
Pharmacodynamics
Ombitasvir is classified as a direct acting antiviral and acts against HCV to inhibit viral replication. |
| Molecular Formula |
C50H67N7O8
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| Molecular Weight |
894.11
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| Exact Mass |
893.505
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| Elemental Analysis |
C, 67.17; H, 7.55; N, 10.97; O, 14.32
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| CAS # |
1258226-87-7
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| Related CAS # |
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| PubChem CID |
54767916
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| Appearance |
White to light yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
1065.6±65.0 °C at 760 mmHg
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| Flash Point |
598.2±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.595
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| LogP |
6.29
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
16
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| Heavy Atom Count |
65
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| Complexity |
1540
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| Defined Atom Stereocenter Count |
6
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| SMILES |
CC(C)(C)C(C=C1)=CC=C1N2[C@H](C3=CC=C(NC([C@H]4N(C([C@@H](NC(OC)=O)C(C)C)=O)CCC4)=O)C=C3)CC[C@H]2C5=CC=C(NC([C@@H]6CCCN6C([C@@H](NC(OC)=O)C(C)C)=O)=O)C=C5
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| InChi Key |
PIDFDZJZLOTZTM-KHVQSSSXSA-N
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| InChi Code |
InChI=1S/C50H67N7O8/c1-30(2)42(53-48(62)64-8)46(60)55-28-10-12-40(55)44(58)51-35-20-14-32(15-21-35)38-26-27-39(57(38)37-24-18-34(19-25-37)50(5,6)7)33-16-22-36(23-17-33)52-45(59)41-13-11-29-56(41)47(61)43(31(3)4)54-49(63)65-9/h14-25,30-31,38-43H,10-13,26-29H2,1-9H3,(H,51,58)(H,52,59)(H,53,62)(H,54,63)/t38-,39-,40-,41-,42-,43-/m0/s1
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| Chemical Name |
methyl N-[(2S)-1-[(2S)-2-[[4-[(2S,5S)-1-(4-tert-butylphenyl)-5-[4-[[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]phenyl]pyrrolidin-2-yl]phenyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
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| Synonyms |
Viekira Pak (trade name); ABT-267; Ombitasvir(ABT-267); ABT267; CHEBI:85183; 2302768XJ8; ABT267; ABT 267
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.80 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.80 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1184 mL | 5.5922 mL | 11.1843 mL | |
| 5 mM | 0.2237 mL | 1.1184 mL | 2.2369 mL | |
| 10 mM | 0.1118 mL | 0.5592 mL | 1.1184 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02487199 | Completed | Drug: ombitasvir/paritaprevir /ritonavir and dasabuvir Drug: ombitasvir/paritaprevir /ritonavir |
Hepatitis C Virus (HCV) |
AbbVie | September 30, 2015 | Phase 3 |
| NCT02476617 | Completed | Drug: dasabuvir Drug: ribavirin |
Chronic Hepatitis C Hepatitis C (HCV) |
AbbVie | June 2015 | Phase 3 |
| NCT02399345 | Completed | Drug: sofosbuvir (SOF) Drug: ribavirin (RBV) |
Chronic Hepatitis C Virus (HCV Infection Genotype 1) |
AbbVie | March 2015 | Phase 3 |
| NCT02493855 | Completed | Drug: Dasabuvir Drug: Ribavirin (RBV) |
Hepatitis C (HCV) Chronic Hepatitis C |
AbbVie | June 2015 | Phase 2 |
| NCT02581189 | Completed | Drug: Dasabuvir Drug: Ribavirin |
Chronic Hepatitis C | AbbVie | October 13, 2015 |
Alignment of amino acids 1 to 100 of NS5A in the replicon cell lines. Amino acid changes relative to the 1b-Con1 sequence are indicated. Amino acids within each genotype where variants resistant to ombitasvir were selected are highlighted in gray.Antimicrob Agents Chemother.2015 Feb;59(2):979-87. |
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HCV RNA viral load during 3-day monotherapy with ombitasvir in HCV genotype 1-infected treatment-naive patients.Antimicrob Agents Chemother.2015 Feb;59(2):979-87. |
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