# SARS-CoV-2 Treatment: Current Therapeutic Options and the Pursuit of Tailored Therapy
## 6 Lopinavir/Ritonavir  
Lopinavir is a human immunodeficiency virus (HIV) type 1 aspartate protease inhibitor (Tables 2 and 3), while ritonavir (a protease inhibitor, also) is administered with lopinavir to increase its plasma half-life through the inhibition of CYP450. Lopinavir showed in vitro activity against SARS-CoV-2 and, in a clinical trial, the administration of lopinavir/ritonavir did not improve clinical symptoms more than the standard of care (SOC) [29].  
Both RECOVERY and The Solidarity Trial, confirmed that lopinavir/ritonavir is not useful in hospitalized patients with COVID-19 [30,31].  
A previous study performed with eight COVID-19 patients, [PERSON] et al. [60] documented that the median LPV steady state plasma concentration (13.6 \(\mathrm{\SIUnitSymbolMicro g}\)/mL) was below the concentration required for SARS-CoV-2 (16.4 \(\mathrm{\SIUnitSymbolMicro g}\)/mL) [61].  
Therefore, supposing that the lack of any clinical benefit of LPV/RTV was the low dosage, [PERSON] et al. [62], recently randomized 51 COVID-19 patients (30% female; median age of 59 years) to receive a high dosing scheme (LPV/RTV 200/50 mg: four tablets bid as loading dose, then three tablets bid for up to 10 days) or a standard dosing scheme. The authors recorded that the post-loading dose was significantly higher (\(p\) < 0.01) in patients enrolled in the high dosage scheme (LPV 24.9 \(\mathrm{\SIUnitSymbolMicro g}\)/mL; RTV 1.2 \(\mathrm{\SIUnitSymbolMicro g}\)/mL) vs. those in the standard dosing scheme. In contrast, during the maintenance therapy (after day two), the authors failed to document higher plasma LPV levels in patients enrolled in the high dosing scheme vs. the normal dose scheme (12.9 \(\mathrm{\SIUnitSymbolMicro g}\)/mL vs. 13.6 \(\mathrm{\SIUnitSymbolMicro g}\)/mL, respectively). Moreover, the authors documented a gender difference in plasma concentration of both LPV and RTV. In particular, they documented a trend towards a higher LPV concentration in females, while RTV plasma levels were significantly higher in females These differences could be related to body weight, volume of distribution, drug-drug interactions or differences in transporter or enzyme expression. The analysis of the above reported data indicates that it is possible to evaluate that LPV/RTV do not have an antiviral effect in COVID-19 patients at both standard and high dosages. This is particularly important if the patient receives a concomitant treatment with dexamethasone, which is a known CYP3A4 inducer which contributes to the metabolization of LPV (Table 4) [47] and can also increase the ADRs (liver toxicity).  
\begin{table}
\begin{tabular}{c c c c} \hline \hline  & **Effect of the** & **Mechanism of** & **Selection of Drugs Affected** & **Clinical Comment** \\  & **Combination** & **Interaction** & **Silutions** & \\ \hline  & & Alfuzosin, bisoprolol, some statins *, & \\  & Serum level\(\downarrow\)by & & gliptins, ranolazine, antiarrhythmic & Risk for reduced \\  & dexamethasone & & drugs (amiodarone, dronedarone), & efficacy \\  & sone * [42] & CYP3A4 & clarithromycin, rivaroxaban, azoles, & Risk for adverse events, \\  & Serum level\(\uparrow\)by & induction & some antihistamines, some & Potential risk of \\  & remdesivir & CYP3A4 & opioids [63] some antipsychoticschotes, & serotonin syndrome \\  & [4,13,14] and & inhibition & antidepressants, & Possible interactions in \\  & lopinavir/ & & carbamazepine, lopinavir/ritonavir, & transplant recipients \\  & ritonavir [28,47] * & & ivermectin, calcineurin inhibitors, & with COVID-19 [64]. \\  & & mTOR inhibitors & & \\ \hline \hline \end{tabular}
\end{table}
Table 4: COVID-19 drugs as perpetrators of drug-drug interactions.  
However, some phase 3 clinical trials are still ongoing and focusing on use of a combination of these drugs (NCT04403100, NCT04321174).