Medical Pharmacology Chapter 36:  Antiviral Drugs

Protease Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Protease Inhibitors

    • Lopinavir/ritonavir (Kaletra,Aluvia)

    •  

    • Lopinavir	Ritonavir

    • Overview:

      • Lopinavir is a peptide-like HIV protease inhibitor, similar to ritonavir.^2,3,4 

        • However it appears up to an order of magnitude (10 fold) more potent against HIV-1 protease in vitro.

        • The concentration of lopinavir required to inhibit by 50% wild-type HIV protease activity (in the presence of 50@ human serum is about 180 nM (range: 65 nM-290 nM).^2,3,4 

      • Lopinavir is presently the only available protease inhibitor coformulated with ritonavir.

        • Ritonavir inhibits cytochrome P450 CYP3A-mediated lopinavir metabolism which results in increased level of lopinavir availability.

        • Coformulation also has the benefit of reducing the "pill burden" which in turn increases patient compliance.^2,3,4 

    • Mutations: 

      • In treatment-experienced patients development of four or more HIV protease inhibitor resistance mutations appears correlated with reduced viral suppression after starting lopinavir. Mutations that appear most likely to result in resistance include I47A/V V32I and L76V or a substitution of wildtype isoleucine at codon 47 with either alanine or valine, a substitution of wildtype valine at codon 32 with isoleucine and a substitution of wildtype leucine at codon 76 with valine, respectively. Many other mutations appear associated with lopinavir failure in the treatment-experienced group; however, low doses of ritonavir in lopinavir plus ritonavir co-formulation does not appear to select for ritonavir-specific resistance mutations. For treatment naïve patients who fail a first regimen that contains lopinavir, the failure does not appear to be caused by pre-existing HIV protease resistance mutations but rather resistance to other drugs in the protocol.
        Amino acid abbreviations: A:  Alanine C:  Cysteine D:  Aspartate E:  Glutamate F:  Phenylalanine G:  Glycine H:  Histidine I:  isoleucine K:  Lysine L:  Leucine	M:  Methionine N:  Asparagine P:  Proline Q:  Glutamine R:  Arginine S:  Serine T:  Threonine V:  Valine W:  Tryptophan Y:  Tyrosine

    • Pharmacokinetics:

      • Food has limited effect on lopinavir + ritonavir bioavailability following oral dosing.^2,3 

        • Accordingly, the drug combination can be administered with or without food.

      • As noted earlier, the presence of ritonavir is not to inhibit HIV protease but rather to inhibit the microsomal cytochrome P450 isoform enzymic activity, CYP3A4, responsible for lopinavir metabolism.

        • Therefore, although the tablet contains lopinavir: ritonavir at a 4:1 ratio, the plasma concentration favors lopinavir by 20:1.

      • Normally, lopinavir is metabolized by the liver and less than 3% of the drug is found unchanged in the liver.

        • About 90% of plasma drug is the parent compound.

      • To illustrate the importance of ritonavir-boosting, lopinavir plasma concentration when lopinavir is administered by itself is limited.

        • This observation emphasizes the substantial hepatic first-pass effect for  lopinavir.

          • The first-pass effect refers to the extent of drug metabolism when the drug first must pass through the liver thus exposing the drug to the hepatic drug metabolizing systems prior to the drug entering the systemic circulation.

        • Another way of appreciating the magnitude of ritonavir boosting effect on lopinavir is through comparison of lopinavir AUC (area-under-the-curve).

          • A 50 mg of ritonavir dose increases AUC for lopinavir nearly 80 fold.

            • Lopinavir is typically boosted by 200 mg/day ritonavir.

            • Other protease inhibitors, such as atazanavir or dolutegravir are boosted with 100 mg/day of ritonavir.^2,3  

      • There are numerous drug-drug interactions that may affect lopinavir/ritonavir combination therapy.^2,3  

        • For example, delavirdine or darunavir administration elevates lopinavir/ritonavir serum levels.

        • On the other hand, administration of didanosine, efavirenz, nevirapine, tipranavir or nelfinavir decreases lopinavir/ritonavir serum levels.^2,3  

      • There are man contraindicated drugs when these agents are used concurrently with lopinavir/ritonavir.^2,3  

      • These drugs change systemic lopinavir/ritonavir levels and involve numerous drug classes as noted below:

      • Many other agent should be used with caution in the reader is referred to primary texts, PDR, and/or drug inserts for complete listing of contraindicated and use with caution agents.^2,3

      • Contraindicated Drugs when used along with Lopinavir/Ritonavir³

        Antiarrhythmic agents	Flecanide, propafenone
        Sedative-hypnotic agents	Diazepam, alprazolam, lorazepam, trazodone, triazolam, midazolam, Clorazepate
        Antihistamines	Terfenadine, astemizole
        Neuroleptics	Pimozide
        Ergot alkaloids derivatives
        HMG-CoA reductase inhibitors	Simvastatin, lovastatin, atorvastatin, rosuvastatin;
        Anticonvulsants	Phenytoin, phenobarbital
        Oral contraceptives	Ethinyl estradiol/norethindrone acetate
        Other	Cisapride, rifampin, St. John's wort, rifapentine.

      Adverse Effects:

      • The most frequently encountered adverse effects with lopinavir/ritonavir are gastrointestinal in nature including diarrhea, loose stools, nausea and vomiting.² 

        • These effects are less likely when compared with administration of 600 mg twice daily ritonavir but more commonly observed than protocols involving boosted atazanavir and darunavir.

        • Other prominent side effects of lopinavir/ritonavir involve insulin resistance and hyperlipidemia, especially hypertriglyceridemia.⁴ 

          •  In some patients these effects may require pharmacological management.⁴ 

    • Therapeutics: 

      • Lopinavir exhibits antiretroviral capability comparable to that of other potent HIV protease enzyme inhibitors and better efficacy when compared to nelfinavir.²   

        • Even for those patients having failed prior HIV protease inhibitor-containing protocols, lopinavir can still exhibit "considerable" and "sustained" antiretroviral activity.

        • A two  tablet adult lopinavir/ritonavir dose is 400/100 mg respectively.

          • A 4 tablet, once daily 800/200 mg formulation is also available but is not recommended in treatment-experienced patients.²   

      • Lopinavir/ritonavir is approved for administration to pediatric patients ≥ two weeks of age.

        • Dosing may be based in this group on either body surface area or weight. A tablet formulation for pediatric patients may be used in children >6 months old.² 

         

  Abbreviations:  Antiretroviral Drugs, Combinations, and Classifications⁴

  3TC = lamivudine	ABC = abacavir	ARV = antiretroviral	ATV/c = cobicistat-boosted atazanavir	ATV/r = ritonavir-boosted atazanavir ear
  DRV/r= ritonavir-boosted darunavir	DTG = dolutegravir	EFV = efavirenz	EVG/c/TDF/FTC = elvitegravir/cobicistat/tenofovir DF/emtricitabine	FTC = emtricitabine
  LPV/r = ritonavir-boosted lopinavir	RAL = raltegravir	RPV =rilpivirine	RTV = ritonavir	TDF = tenofovir disoproxil fumarate
  INSTI = integrase strand transfer inhibitor	NNRTI = nonnucleoside reverse transcriptase inhibitor	NRTI = nucleoside reverse transcriptase inhibitor	PI = protease inhibitor	CrCl = creatinine clearance

   "Rating Scheme for Recommendation"⁴

  Strength of Recommendation	Quality of Evidence for Recommentation
  A:  Strong recommendation for the statement	I:  One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
  B:  Moderate recommendation for the statement	II:  One or more well-designed, non-randomized trials or observational cohort studies with long-term clinical outcomes
  C:  Optional recommendation for the statement	III.  Expert opinion