Summary of everything that’s important from the insert and of the entire course Preclinical Drug Research (18/20): This is a compact summary of both the insert of Norvir and the insert of Omeprazole plus a summary of the whole course called “Preclinical Drug Research” (slides, lectures, and a...
Norvir®
Norvir (ritonavir) is an inhibitor of HIV protease with activity against the Human
Immunodeficiency Virus (HIV). Its molecular formula is C37H48N6O5S2, and its
molecular weight is 720.95.
Ritonavir is a white-to-light-tan
powder. Ritonavir has a bitter metallic
taste. It is freely soluble in methanol
and ethanol, soluble in isopropanol and
practically insoluble in water.
Norvir soft gelatin capsules are available for oral administration in strength of 100 mg
ritonavir with the following inactive ingredients: butylated hydroxytoluene, ethanol,
gelatin, iron oxide, oleic acid, polyoxyl 35, castor oil, and titanium dioxide.
Norvir oral solution is available for oral administration as 80 mg/mL of ritonavir in a
peppermint and caramel flavored vehicle.
Clinical Pharmacology
Microbiology
Mechanism of action: Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and
HIV-2 proteases. Inhibition of HIV protease leads to production of non-infectious
immature HIV particles.
Antiviral Activity in vitro: The activity of ritonavir was assessed in vitro in acutely
infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The IC50 of
viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the
cells employed. In MT4 cells, ritonavir demonstrated additive effects against HIV-1
in combination with either zidovudine or didanosine. Cytotoxicity studies on several
cell lines showed that >20µM was required to inhibit cellular growth by 50% resulting
in an in vitro therapeutic index of at least 1000.
Resistance: HIV-1 isolates with reduced susceptibility to ritonavir have been selected
in vitro. Genotypic analysis of these isolates showed mutations in the HIV protease
gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46
(Met to Ile).
Cross-Resistance to other anti-retrovirals: Among protease inhibitors, variable
cross-resistance has been recognized. Serial HIV isolates during ritonavir therapy
showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a
concordant decrease in susceptibility to saquinavir in vitro when compared to
matched baseline isolates. However, isolates from two of these patients demonstrated
decreased susceptibility to indinavir in vitro (8-fold). Cross-resistance between
ritonavir and reverse transcriptase inhibitors is unlikely.
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, Safety pharmacology:
[Not mentioned – what set of experiments belong to this package?]
Pharmacokinetics
The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-
infected patients.
Absorption: The absolute bioavailability of ritonavir has not been determined. After a
600 mg dose of oral solution, peak concentrations of ritonavir were achieved
approximately 2 hours and 4 hours after dosing under fasting and non-fasting
conditions, respectively.
Effect of Food on Oral Absorption: under non-fasting conditions, peak ritonavir
concentrations decreased 23% and the extent of oral absorption decreased 7% relative
to fasting conditions. After a single 600 mg dose under non-fasting conditions, the
soft gelatin capsule and oral solution formulations yielded mean AUC’s of 121.7 ±
53.8 and 129.0 ± 39.3 µg•h/mL.
Metabolism: Nearly all plasma radioactivity after a single oral dose of 14C-ritonavir
was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified
in human urine and feces. The isopropylthiazole oxidation metabolite is the major
metabolite and has antiviral activity similar to that of parent drug; however, the
concentrations of this metabolite in plasma are low. In vitro studies utilizing human
liver microsomes have demonstrated that CYP3A is the major isoform involved in
ritonavir metabolism, although CYP2D6 also contributes.
Elimination: In a study using 14C-ritonavir oral solution, 11.3% of the dose was
excreted into the urine, with 3.5% of the dose excreted as unchanged parent drug;
86.4% of the dose was excreted in the feces with 33.8% of the dose excreted as
unchanged parent drug. [What type of study was used ?] Upon multiple dosing,
ritonavir accumulation is less than predicted from a single dose possibly due to a time
and dose-related increase in clearance.
Ritonavir Pharmacokinetic Characteristics
Parameter Values (Mean ± SD)
Cmax SS 11.2 ± 3.6 µg/mL
Ctrough SS 3.7 ± 2.6 µg/mL
t½ 3-5h
CLR < 0.1 L/h
RBC/Plasma Ratio 0.14
Percent Bound* 98 to 99%
*Primarily bound to human serum albumin and alpha-1 acid glycoprotein.
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