Page 652 - Basic _ Clinical Pharmacology ( PDFDrive )

638 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

INHIBITION OF MICROSOMAL AGENTS UNDER DEVELOPMENT
TRIGLYCERIDE TRANSFER PROTEIN CETP INHIBITION

Microsomal triglyceride transfer protein (MTP) plays an
essential role in the addition of triglycerides to nascent VLDL Cholesteryl ester transfer protein (CETP) transfers cholesteryl
in liver, and to chylomicrons in the intestine. Its inhibition esters from mature, large diameter HDL particles to triglyceride-
decreases VLDL secretion and consequently the accumulation rich lipoproteins that ultimately deliver the esters to liver whence
of LDL in plasma. An MTP inhibitor, lomitapide, is available both cholesterol and bile acids can be eliminated into the intes-
but is currently restricted to patients with homozygous familial tine. Inhibition of CETP leads to accumulation of mature HDL
hypercholesterolemia. It causes accumulation of triglycerides in particles and diminution of the transport of cholesteryl esters to
the liver in some individuals. Elevations in transaminases can liver. The accumulation of large HDL particles does not have the
occur. Patients must maintain a low fat diet to avoid steator- cardioprotective effect anticipated on the basis of epidemiologic
rhea and should take steps to minimize deficiency of essential studies. Some reduction of LDL-C can be achieved and choles-
fat-soluble nutrients. Lomitapide is given orally in gradually terol efflux capacity enhanced. Thus far no drug (eg, torcetrapib,
increasing doses of 5- to 60-mg capsules once daily 2 hours anacetrapib) in this class has been approved.
after the evening meal. It is available only through a restricted
(REMS) program for patients with homozygous familial AMP KINASE ACTIVATION
hypercholesterolemia.
AMP-activated protein kinase acts as a sensor of energy status in
cells. When increased ATP availability is required, AMP kinase
ANTISENSE INHIBITION OF APO increases fatty acid oxidation and insulin sensitivity, and inhibits
B-100 SYNTHESIS cholesterol and triglyceride biosynthesis. Although the trials to
date have been directed at decreasing LDL-C levels, AMP kinase
Mipomersen is an antisense oligonucleotide that targets apo activation may have merit for management of the metabolic syn-
B-100, mainly in the liver. It is important to note that the apo drome and diabetes. An agent combining AMP kinase activation
B-100 gene is also transcribed in the retina and in cardiomyo- and ATP citrate lyase inhibition is in clinical trials.
cytes. Subcutaneous injections of mipomersen reduce levels of
LDL and Lp(a). Mild to moderate injection site reactions and CYCLODEXTRINS
flu-like symptoms can occur. The drug is available only for use
in homozygous familial hypercholesterolemia through a restricted These are circular sugar polymers that can solubilize hydrophobic
(REMS) program. drugs for delivery and are approved for this purpose. They can
also solubilize cholesterol from tissue sites such as arteriosclerotic
PCSK9 INHIBITION plaque. Early stage animal studies on this potential therapeutic
activity are in progress.
Development of inhibitors of proprotein convertase subtilisin/
kexin type 9 (PCSK9) followed on the observation that loss TREATMENT WITH DRUG
of function mutations result in very low levels of LDL and no COMBINATIONS
apparent morbidity. Therapeutic agents currently available in
this class are humanized antibodies to PCSK9 (evolocumab, Combined drug therapy is useful (1) when VLDL levels are signif-
alirocumab). LDL reductions of up to 70% at the highest icantly increased during treatment of hypercholesterolemia with a
doses have been achieved with these agents when administered resin; (2) when LDL and VLDL levels are both elevated initially;
subcutaneously every two weeks. (Evolocumab can also be (3) when LDL or VLDL levels are not normalized with a single
given monthly at a higher dose). Triglycerides and apo B-100 agent, or (4) when an elevated level of Lp(a) or an HDL deficiency
are reduced, and Lp(a) levels decrease by about 25%. Rarely, coexists with other hyperlipidemias. The lowest effective doses
hypersensitivity reactions have occurred. Local reactions at the should be used in combination therapy and the patient should be
injection site, upper respiratory and flu-like symptoms have monitored more closely for evidence of toxicity. In combinations
been observed more frequently. Use of these agents is restricted that include resins, the other agent (with the exception of niacin)
to patients who have familial hypercholesterolemia or clinical should be separated temporally to ensure absorption.
atherosclerotic cardiovascular disease who require additional
reduction of LDL. They are given with diet and maximal toler- FIBRIC ACID DERIVATIVES & BILE
ated statin and/or ezetimibe. Development of small molecules ACID-BINDING RESINS
and antisense oligonucleotides to inhibit PCSK9 is underway.
Studies of PCSK9 inhibition should be approached with cau- This combination is sometimes useful in treating patients with
tion because of its established role in normal cell biology. These familial combined hyperlipidemia who are intolerant of niacin or
agents are very expensive. statins. However, it may increase the risk of cholelithiasis.