Download Clinical Trials - Ritonavir

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Ritonavir
Introduction
As of the end of 1999, an estimated 34.3 million people worldwide -- 33.0
million adults and 1.3 million children younger than 15 years -- were living with
HIV/AIDS. More than 71 percent of these people (24.5 million) live in Sub-Saharan
Africa; another 16 percent (5.6 million) live in South and Southeast Asia.1 (1from:
http://www.niaid.nih.gov/factsheets/aidsstat.htm). From this HIV/AIDS statistics, the
number HIV infections in South and Southeast Asia are secondary high number of
HIV infections. This study has the objective for bringing down drug prices, either
through company discounts by setup the company in Thailand for cheaper HIV-drug.
In 29 February 1996 - Project Inform today announced its support for
accelerated approval of the Abbott protease inhibitor ritonavir (Norvir) for all HIVinfected people for whom therapy is indicated. The manufacturer reported that the
drug produced slightly less than a 43% reduction in the death rate and a 58%
reduction in the rate of new infections or death after four months of use. More
importantly in clinical trials, the development of drug resistance after used this drug is
concerning. Since resistance to this drug confers resistance to most other protease
inhibitors. There is good reason to fear that such a use of the drug may lead only to
short-term benefit followed quickly by long-term multi-drug cross resistance to many
of the key products in the field of protease inhibitors. This report presence the general
data of Ritonavir.
With record speed, ritonavir (Norvir(TM)), Abbott Laboratories' protease
inhibitor, was approved by the FDA on March 1, 1996 (one day after approval was
recommended by the FDA's Antiviral Drugs Advisory Committee). Ritonavir is also
known as "Norvir." It belongs to a class of drugs called protease inhibitors. Protease
inhibitors are used for the treatment of HIV infection usually in combination with
other anti-HIV drugs. Ritonavir does not eradicate or kill the entire virus in the body,
but helps reduce the rate at which the virus reproduces itself. Protease is one of HIV’s
enzymes; its role is to break up the long chains of HIV proteins that are produced
inside infected cells. Protease inhibitors prevent protease from cutting the protein
chains into shorter pieces that HIV needs to make new particles. By working in this
way protease inhibitors reduce the number of new active copies of HIV that can infect
other cells.
Genetic Name : Ritonavir
Alias/Trade Name : Norvir
Therapeutic Classification : Antriretroviral Protease Inhibitor
Description
Ritonavir (trade name Norvir) is one of a new group of anti-HIV drugs called
protease inhibitors. Ritonavir is used, alone or in combination with other medicines,
in the treatment of the infection caused by the human immunodeficiency virus (HIV).
HIV infection leads to the destruction of CD4 (T) cells, which are important to the
immune system. After a large number of CD4 (T) cells have been destroyed, acquired
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immune deficiency syndrome (AIDS) develops. So, HIV is the virus that causes
acquired immune deficiency syndrome (AIDS). These drugs work by blocking a part
of HIV called protease. When protease is blocked, HIV makes copies of itself that
can't infect new cells.
Ritonavir is chemically designated as 1Hydroxy-2-mthyl-5-(1-methylethyl)-1[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12tetraazatridecan-13-oic acid,5-thiazolylmethyl ester,[5S-(5S*,8R*,10R*,11R*)].Its
molecular formula is C37H48N6O5S2 , and its molecular weight is 720.95 and a melting
point is 61-63C.
Ritonavir is a white to light-tan, very fine powder. It is a freely soluble in
methanol and ethanol, soluble in isopropanol and practically insoluble in water. It has
a bitter metallic taste.
Ritonavir is sold in two forms, capsules and oral solution. It should be taken
with meals if possible
 Soft gelatin capsules are white capsules available for oral administration in
a strength of 100 mg ritonavir with the following inactive ingredients:
butylated hydroxytoluenr, ethanol, gelatin,iron oxide.oleic acid,polyoxyl
35 castor oil, and titanium dioxide.
 Oral solution is an orange-colored liquid, supplied in amber-colored,
multi-dose bottles containing 600 mg ritonavir per 7.5 mL marked dosage
cup (80 mg/mL). Oral solution also contains ethanol, water, polyoxyl 35
castor oil, propylene glycol, anhydrous citric acid to adjust pH, saccharin
sodium, peppermint oil, creamy caramel flavoring, and FD&C Yellow
No.6.
Clinical Pharmacology
Ritonavir is approved for the treatment of HIV in both adults and children.
New guidelines from the Public Health Service state that combination therapy with
three anti-HIV drugs is currently the most effective treatment for HIV. If you've been
taking anti-HIV drugs for a while, the guidelines recommend changing to at least one
other new anti-HIV drug when starting a protease inhibitor. Ideally all two new antiHIV drugs should be started at the same time as the protease inhibitor.
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Microbiology
Mechanism of action
Ritonavir is a selective, competitive inhibitor of HIV protease. This enzyme
plays an essential role in the HIV replication cycle and the formation of infectious
virus. By interfering with the formation of essential proteins and enzymes, ritonavir
blocks the maturation of the virus and causes formation of nonfunctional, immature,
noninfectious virions. The antiviral activity of ritonavir does not depend on
intracellular conversion to an active metabolite. HIV protease inhibitors, including
ritonavir, act at different stages of the HIV replication cycle than the
dideoxynucleoside and nonnucleoside reverse transcriptase inhibitor. Ritonavir
exchibits cytotoxic properties at concentrations at least 1000x greater than those
required for antiretroviral activity.
Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2
proteases. The HIV protease protein has been shown to be an essential part of the
virion's life cycle and is responsible for cleaving the gag-pol polyprotein into its
component parts. Inhibition of the protease results in loss of the gag protein (p24),
accumulation of unprocessed full-length gag-pol protein, and the emergence of
"defective" particles of HIV.
Resistance
HIV does not always make perfect copies of itself. With billions of viruses
being made every day, lots of small, random differences almost like mistakes can
happen in any new virus that gets made. The differences are called mutations.
Mutations that change the parts of the virus the drugs are meant to stop can keep the
drugs from working. When a drug no longer works against HIV, this is called drug
resistance. The virus with the mutation is resistant to the drug.
Resistance to ritonavir has been produced in vitro by HIV-1 isolation, with
mutation of HIV protease seeming to be the principle mechanism of resistance.
Genotypic analysis of these isolates showed mutations in the HIV protease gene at
amino position 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile).
Phenotypic and genotypic changes in HIV isolates treated with ritonavir were
monitored in phase I/II trials over a period of 3 to 32 weeks. The clinical relevance of
phenotypic and genotypic changes associated with ritonavir therapy has not been
established. Some HIV mutations were also found in patient groups on
MONOTHERAPY. The antriretroviral effects of ritonavir and other agents such as
dideoxynucleosides are additive or synergistic against HIV-1.
Long term use of this agent ALONE leads to the emergence of resistant
viruses. As such, this agent should never be used as MONOTHERAPY but in
combination with a RTI.
Cross-resistance
Cross-resistance occurs when HIV that is resistant to one drug automatically
becomes resistant to another similar drug. The issue of cross-resistance between
protease inhibitors is complex. High-level resistance to ritonavir may limit the success
of future use of saquinavir, indinavir or nelfinavir. To delay or avoid resistance,
switch all drugs in a ritonavir-containing regimen at the first sign of drug failure.
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Cross-resistance between ritonavir and dideoxynucleoside or nonnucleoside
transcriptase inhibitors is highly unlikely because these drugs have different target
enzymes.
Pharmacokinetics
(See Appendix I)
Absorption, Bioavailability, and Food effect
The absolute bioavailability of ritonavir has not been determined. Ritonavir is
well absorbed following oral administration; peak plasma concentrations come within
2 and 4 hours after dosing under fasting or non-fasting conditions, respectively. When
the oral solution was given under non-fasting conditions, peak ritonavir concentration
decrease 23% and extent of absorption decrease 7% relative to fasting conditions.
Relative to fasting conditions, the extent of absorption of ritonavir from the soft
gelatin capsule formulation was 13% higher when administrated with a meal.
Distribution and Elimination
This medicine does not appear to be metabolized on first pass through the
liver. Ritonavir is 98-99% plasma bound. The medicine is metabolized in the liver;
five metabolites have been identified in urine and feces. The isopropylthiazole
oxidation metabolite (M-2) is the major metabolites and has antiviral activity similar
to that of parent drug; however, the concentrations of this metabolite in plasma are
low. Some 86.4% of a single oral 600 mg dose is eliminated through the feces with
33.8% of the dose excreted as unchanged parent drug and 11.3% is excreted in urine
with 3.5% of the dose excreted as unchanged parent drug. Upon multiple dosing,
ritonavir accumulation is less than predicted from a single dose possibly due to a time
and dose-related increase in clearance.
Metabolism
Ritonavir undergoes cytochrome P450-mediated biotransformation in human
liver microsomes to three major metabolites, Ml, M2 and M11, with wide
interindividual variation in the rates of metabolite formation. Both CYP3A and
CYP2D6 contributed to the formation of M2. None of the typical CYP3A
substrates/inhibitors (e.g., ketoconazole, troleandomycin) were able to completely
inhibit ritonavir metabolism, even at high concentrations. Ritonavir was found to be a
potent inhibitor of CYP3A-mediated biotransformations. Ritonavir was also found to
be an inhibitor of the reactions mediated by CYP2D6 and CYP2C9/10. The results
indicate the potential for in vivo inhibition of the metabolism by ritonavir of drugs that
are CYP3A, CYP2D6 and, to a lesser extent, CYP2C9/10 substrates.
Metabolic inactivation of CYP3A by ritonavir explains the improved
bioavailability and pharmacokinetics of ritonavir and the sustained elevation of blood
levels of other, concomitantly administered, substrates of CYP3A.
Special Populations
Hepatic and Renal Impairment: Ritonavir pharmacokinetics in patients with
hepatic or renal insufficiency have not been investigated, however since renal
clearance is negligible, a decrease in total body clearance is not expected in patients
with renal insufficiency.
Gender, Race and Age
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No-age related pharmacokinetic differences have been observed in adult
patients (18-63 years). Ritonavir have not been studies specifically in older people. In
healthy males and females showed no statistically significant differences in the
pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been
identified.
AIDS-Related Uses
Ritonavir is indicated in adults in combination with other antiretroviral agents
for the treatment of HIV infection. This indication is based on the results from a study
in-patient with advanced HIV disease that showed a reduction in both mortality and
AIDS-defining clinical events. Ritonavir also has been approved by the FDA for use
in children between the ages of 2 and 16 based on safety and pharmacokinetic data.
Drug Interactions
Ritonavir is broken down by the liver. It can interact with other drugs that use
the liver. Combining these drugs can change the amount of each drug in your
bloodstream and cause an under- or overdose. Drugs to watch out for include several
antihistamines, sedatives, and anti-fungal drugs.
Drug interactions may occur when ritonavir is coadministered with a wide
variety of other drugs mostly because of pharmacokinetic interactions. Ritonavir is
metabolized by isoforms of the cytochrome P450 enzyme system. When it is
administered with other drugs that are extensively metabolized by these isoenzymes,
competition for the isoenzymes may occur, there may decrease metabolism of these
drugs, and their plasma concentration may be elevated.
Ritonavir is expected to increase plasma levels of the following drugs:
Aminodarone, Astemizole, Bepridil, Bupropion, Cisapride, Clozapine, Erythromycin,
Meperidine, Methylphenidate, Phenothiazines, Piroxicam, Propafenone,
Propoxyphene, Quinidine, Rifabutin, Terfenadine and Warfarin. This may to an
increase risk of arrhythmias, hematological complications, seizures and other serious
side effects. Coadministration of ritonavir and ergotamine or dihydroergotamine has
been associated with acute ergot toxicity. Ritonavir may produce a decrease in the
plasma levels of the following drugs: Atovaquone, Clofibrate, Daunorubicin,
Diphenoxylate, Metoclopramide, and Sedatives/hyponotics. Coadministration of
ritonavir with the following drugs may cause extreame sedation and respiratory
depression: Alprazolam, Clorazepate, Diazepam, Estazolam, Flurazepam, Midazolam,
Trizolam, and Zolpidem. The following drugs reduces blood levels of ritonavir:
Rifampin, also known as Rimactane , Rifadin , Rifater and Rifamate. And the
following drugs require dose reduction if taken with ritonavir: Mycobutin
(Rifabutin) and Viagra. Furthermore, tobacco use has been found to decrease
ritonavir blood levels by 18 percent.(Ritonavir therapy see in Appendix II & III)
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Drug Combination Therapy
Ritonavir has been studied in combination with AZT/ddC, in which the
greatest viral load decreases were seen. Other combinations are now being studied and
should be discussed with doctor. In deciding which combination to take, think about
possible side effects and if possible, look for a combination that you have not taken
before.
When taken protease inhibitors together, ritonavir increases the amount of the
protease inhibitor saquinavir (Fortovase) in the body. Because the level is higher than
usual, the dose of both drugs is lowered. When taken together, the doses are 400 mg
of Fortovase and 400 mg of ritonavir twice a day. This combination, along with one
or two nucleoside analog drugs (AZT, ddI, ddC, d4T, 3TC) is listed as a possible first
HIV treatment in the new Public Health Service guidelines on how to use HIV drugs.
Other studies are now investigating lower doses of ritonavir taken with saquinavir,
and a once-daily combination of these two drugs. Several other studies are
investigating low doses of ritonavir in combination with the protease inhibitors
indinavir (Crixivan) and amprenavir (Agenerase).
Contraindications
Because ritonavir is principally metabolized by the liver, it needs to be used
with caution in patients with impaired liver functions. Ritonavir may not be right for
everyone, including people with liver disease, hepatitis, or hemophilia.
Hemophilia
There have been reports of increased bleeding when patients with type A or
Type B hemophilia were treated with protease inhibitors. A causal relationship has
not been established.
Hepatic Reactions
Ritonavir may be increased risk for transaminase elevation in-patients with
underlying hepatitis B or C. Therefore, caution should be exercised when
administering ritonavir to pre-existing liver diseases, liver enzyme abnormalities, or
hepatitis.
Pancreatitis
Pancreatitis has been observed in-patients receiving ritonavir therapy,
including those who developed high triglycerides.
Diabetes Mellitus/Hyperglycemia
Some patient required either initiation or dose adjustments of insulin or oral
hypoglycemic agents for treatment of these events. In some cases, diabetic
ketoacidosis has occurred. In those patients who discontinued protease inhibitor
therapy, hyperglycemia persisted in some cases.
Allergic Reactions
Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and
angioedema have been reported.
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Pregnancy, Fertility, and Reproduction
Studies have not been done in humans. However, in animal studies ritonavir
has been found cause reduced weight and delayed growth in the infants. Ritonavir did
not cause birth defects in animal studies. However, no adequate and well-controlled
studies in pregnant women have been performed. Because animal reproduction studies
are not always predictive of human response, it is not known whether this drug
crosses the placenta. However, this drug should be used during pregnancy only if
needed.
Nursing Mothers
It is also not known whether ritonavir is distributed into human milk but the
CDC advises HIV-positive women in general not to breast-feed, in order to avoid
virus transmission to their infants. The evaluation of ritonavir as an antiviral drug in
pediatric HIV patients is ongoing.
Carcinogenesis and Mutagenesis
Long-term carcinogenesis studies in rats and mice have not yet been
completed. However, ritonavir was not mutagenic or clastogenic in a battery of in vivo
and in vitro assay by bacteria using.
Adverse Effects/Toxicity
Adverse effects most frequently reported include fatigue, asthenia, nausea,
diarrhea, loss of appetite, vomitting, anorexia, abdominal pain, taste perversion, and
tingling sensation or numbness in the hands, feet, or around the lips, headache,
dizziness, circumoral and peripheral paresthesias. Less common adverse effects
include fever, headache, malaise, vasodilation, constipation, dyspepsia, flatulence,
local throat irritation, increase in creatine phosphokinase, hyperlipidemia, myalgia,
dizziness, insomnia, somnolence, abnormal thinking, pharyngitis, rash, and sweating.
Other adverse events reported occurred in less than 2% of the patients studied; these
included cardiovascular, GI, endocrine, CNS, hematological and lymphatic systems,
and dermatological reactions. Ritonavir has also been associated with alterations in
triglyceride, AST, ALT, GGT, CPK, and uric acid laboratory test values.
Managing side effects
Ritonavir should be taken with a full high-protein, high-fat meal if possible.
Anecdotal reports also suggest that taking ritonavir right after a meal with yogurt may
help reduce side effects. If side effects continue and cannot tolerate the drug, it may
be an idea to consider another protease inhibitor such as indinavir (Crixivan) or
saquinavir (Invirase).
Dosage and Administration
The dose of ritonavir will be different for different patients. The company that
makes ritonavir, Abbott Laboratories, recommends building up the dose of ritonavir
slowly over a few days when first starting the drug. People can start at 300 mg twice a
day, and then move on to 400 mg twice a day after a few days, continuing until you
reach the recommended dose of 600 mg twice a day. It is very important that you take
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no more than 14 days to build up the dose, as this could help HIV get resistant to the
effects of the drug. If you can't take the full dose, the lowest dose that can be used is
500 mg twice a day, and this must be in combination with other anti-HIV drugs. The
dosage for children is based on the child's size.
For oral capsules form:
 Adults - 600 mg twice a day
 Children – This oral dosage form is usually not used for children
For oral solution form:
 Adults – This oral dosage form is usually not used for adults
 Children 2 years of age and older – Dose is based on body size and must
be determined by doctor
 Children less than 2 years of age – Use and dose must be determined by
doctor
In addition, patients initiating combination regimens with ritonavir and
nucleosides may improve gastrointestinal tolerance by initiating ritonavir alone and
subsequently adding nucleosides before completing two weeks of ritonavir
monotherapy. Patients should be informed to take ritonavir every day as prescribed.
Patients should not alter the dose or discontinue ritonavir without consulting their
doctor. If a dose is missed, patients should take the next dose as soon as possible.
However, if a dose is skipped, the patients should not double the next dose. Ritonavir
is recommended to be taken with food, if possible.
Prediatric Patients
The recommended dosage of ritonavir is 400 mg/M2 twice daily by mouth and
should not exceed 600 mg twice daily. Ritonavir should be start 250 mg/m2 and
increase at 2 to 3 day intervals by 50 mg/m2 twice daily.
Pedictric Dosage Guidelines
Body Surface
Area* (m2)
0.25
0.50
1.00
1.25
1.50
Twice Daily Dose
250 mg/m2
0.8 mL
(62.5 mg)
1.6 mL
(125 mg)
3.1 mL
(250 mg)
3.9 mL
(312.5 mg)
4.7 mL
(375 mg)
Twice Daily Dose
300 mg/m2
0.9 mL
(75 mg)
1.9 mL
(150mg)
3.75 mL
(300 mg)
4.7 mL
(375 mg)
5.6 mL
(450 mg)
*
Twice Daily Dose
350 mg/m2
1.1 mL
(87.5 mg)
2.2 mL
(175 mg)
4.4 mL
(350 mg)
5.5 mL
(437.5 mg)
6.6 mL
(525 mg)
Twice Daily Dose
400 mg/m2
1.25 mL
(100 mg)
2.5 mL
(200 mg)
5 mL
(400 mg)
6.25 mL
(500 mg)
7.5 mL
(600 mg)
Body surface area can be calculated with the following equation:
Ht (cm) xWt(kg)
BSA (m2)
=
3600
Storage Instructions
Ritonavir comes in capsule and liquid formulations. The capsules must be kept
refrigerated at 2-8C (36-46F) and protected from light. Store oral solution is also
recommended, and avoids exposure to excessive heat. Refrigerated storage of soft
gelatin capsules by patients is recommended, but not required if kept in a cool place
and used within 30 days and stored below 25C (77F).
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Treatment failure
A 44% rate of virological treatment failure was reported with protease
inhibitors in a fast-track paper just published in AIDS. The failure rate varied by
agent: 64% for saquinavir, 38% for ritonavir, and 30% for indinavir.
Conclusion
Ritonavir is not a cure for HIV infection. People treated with ritonavir may
continue to acquire illnesses associated with advanced HIV infection, including
opportunistic infections. People react to medicines in different ways. Some people
have mild effects or no symptoms at all, while others may have many side effects or
severe symptoms. Even when side effects occur, they can be temporary, or get better
over time. Ritonavir may not be right for everyone, including people with liver
disease, hepatitis, or hemophilia. Redistribution/accumulation of body fat has been
observed inpatients receiving protease inhibitors. Elevated blood sugar levels have
been reported inpatients taking protease inhibitors. Allergic reactions ranging from
mild to severe have been reported. Pancreatitis has been observed inpatients receiving
ritonavir therapy, including those who developed high triglycerides. Furthermore,
other concerns are that ritonavir has little safety data beyond six months at this time. It
strongly inhibits a specific liver enzyme, which presumably is in the body for a
reason; blocking this enzyme for extended periods might cause problems. And we
have heard more anecdotal reports of side effects with ritonavir than with the other
protease inhibitors. There is also the problem of resistance and cross resistance
(especially cross resistance to Merck's Crixivan; Indinavir); this may be minimized
by optimal use of the drug , by combining it with two or more other antivirals, and by
not missing doses.
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Reference:
http://www.immunet.org/immunet/atn.nsf/page/a-243-02
http://www.sti.healthcare.org.uk/hiv/h_medication/ritonavir.htm
http://www.aegis.com/factshts/network/simple/riton.html
http://www.aidsinfonyc.org/network/simple/resistance.html
http://health.yahoo.com/health/Drugs_Tree/Medication_or_Drug/0711
http://www.dml.georgetown.edu/depts/pharmacology/p450ref6.html
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=9616191&form=6&db=m&Dopt=b
http://www.pharminfo.com/pubs/pnn/pnn18.html#2a
http://www.thaimedscape.com/aids/aids2.html
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