Limits...
Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro(®)): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B.

Geary RS, Baker BF, Crooke ST - Clin Pharmacokinet (2015)

Bottom Line: It does not exhibit PK-based drug-drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs.Furthermore, mipomersen does not prolong the corrected QT (QTc) interval.There have been no ethnic- or gender-related differences in PK observed.

View Article: PubMed Central - PubMed

Affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA, rgeary@isisph.com.

ABSTRACT
Mipomersen (Kynamro(®)), a second-generation 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO), inhibits the synthesis of apolipoprotein B (apoB) and is indicated in the US as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH) at a dose of 200 mg subcutaneously (SC) once weekly. The pharmacokinetic (PK) properties of mipomersen are generally consistent across all species studied, including mouse, rat, monkey, and humans. After SC administration, mipomersen is rapidly and extensively absorbed. It has an apparent plasma and tissue terminal elimination half-life of approximately 30 days. Mipomersen achieves steady-state tissue concentrations within approximately 4-6 months of once-weekly dosing. It does not exhibit PK-based drug-drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs. Furthermore, mipomersen does not prolong the corrected QT (QTc) interval. There have been no ethnic- or gender-related differences in PK observed. In clinical trials, both as a single agent and in the presence of maximal lipid-lowering therapy, mipomersen has demonstrated significant dose-dependent reductions in all measured apoB-containing atherogenic lipoproteins. Overall, mipomersen has well-characterized PK and pharmacodynamic properties in both animals and humans, and is an efficacious adjunct treatment for patients with HoFH.

Show MeSH

Related in: MedlinePlus

Mean percentage change from baseline (week 0) to primary efficacy timepoint for (a) LDL cholesterol, (b) apoB, and (c) Lipoprotein(a). Error bars indicate 95 % CI. Reproduced from Raal et al. [18], with permission. apoB apolipoprotein B, LDL low-density lipoprotein
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4305106&req=5

Fig7: Mean percentage change from baseline (week 0) to primary efficacy timepoint for (a) LDL cholesterol, (b) apoB, and (c) Lipoprotein(a). Error bars indicate 95 % CI. Reproduced from Raal et al. [18], with permission. apoB apolipoprotein B, LDL low-density lipoprotein

Mentions: The four phase III studies enrolled patients with homozygous FH (N = 51) [18], severe hypercholesterolemia (N = 58) [36], heterozygous FH (N = 124) [37] and severe hypercholesterolemia in patients at high cardiovascular risk (N = 158) [38]. All patients in these four trials were on maximally tolerated lipid-lowering therapy and had an average of more than two prior cardiovascular events. The percentage change from baseline in LDL-C in patients treated with mipomersen 200 mg SC weekly ranged from −25 to −37 %, while those treated with placebo ranged from −5 to +13 % (Table 3). The effects on LDL-C, apoB and Lp(a) levels in homozygous FH patients after 26 weeks of treatment with mipomersen compared with placebo are shown in Fig. 7.Fig. 7


Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro(®)): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B.

Geary RS, Baker BF, Crooke ST - Clin Pharmacokinet (2015)

Mean percentage change from baseline (week 0) to primary efficacy timepoint for (a) LDL cholesterol, (b) apoB, and (c) Lipoprotein(a). Error bars indicate 95 % CI. Reproduced from Raal et al. [18], with permission. apoB apolipoprotein B, LDL low-density lipoprotein
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4305106&req=5

Fig7: Mean percentage change from baseline (week 0) to primary efficacy timepoint for (a) LDL cholesterol, (b) apoB, and (c) Lipoprotein(a). Error bars indicate 95 % CI. Reproduced from Raal et al. [18], with permission. apoB apolipoprotein B, LDL low-density lipoprotein
Mentions: The four phase III studies enrolled patients with homozygous FH (N = 51) [18], severe hypercholesterolemia (N = 58) [36], heterozygous FH (N = 124) [37] and severe hypercholesterolemia in patients at high cardiovascular risk (N = 158) [38]. All patients in these four trials were on maximally tolerated lipid-lowering therapy and had an average of more than two prior cardiovascular events. The percentage change from baseline in LDL-C in patients treated with mipomersen 200 mg SC weekly ranged from −25 to −37 %, while those treated with placebo ranged from −5 to +13 % (Table 3). The effects on LDL-C, apoB and Lp(a) levels in homozygous FH patients after 26 weeks of treatment with mipomersen compared with placebo are shown in Fig. 7.Fig. 7

Bottom Line: It does not exhibit PK-based drug-drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs.Furthermore, mipomersen does not prolong the corrected QT (QTc) interval.There have been no ethnic- or gender-related differences in PK observed.

View Article: PubMed Central - PubMed

Affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA, rgeary@isisph.com.

ABSTRACT
Mipomersen (Kynamro(®)), a second-generation 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO), inhibits the synthesis of apolipoprotein B (apoB) and is indicated in the US as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH) at a dose of 200 mg subcutaneously (SC) once weekly. The pharmacokinetic (PK) properties of mipomersen are generally consistent across all species studied, including mouse, rat, monkey, and humans. After SC administration, mipomersen is rapidly and extensively absorbed. It has an apparent plasma and tissue terminal elimination half-life of approximately 30 days. Mipomersen achieves steady-state tissue concentrations within approximately 4-6 months of once-weekly dosing. It does not exhibit PK-based drug-drug interactions with other concomitant medications, either involving competition for plasma protein binding or alterations in disposition of any evaluated drugs. Furthermore, mipomersen does not prolong the corrected QT (QTc) interval. There have been no ethnic- or gender-related differences in PK observed. In clinical trials, both as a single agent and in the presence of maximal lipid-lowering therapy, mipomersen has demonstrated significant dose-dependent reductions in all measured apoB-containing atherogenic lipoproteins. Overall, mipomersen has well-characterized PK and pharmacodynamic properties in both animals and humans, and is an efficacious adjunct treatment for patients with HoFH.

Show MeSH
Related in: MedlinePlus