Introduction
It is identified in the literature that considerable proportion of patients infected with severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) are using combination of lopinavir (LPV) and ritonavir (RTV) as first line antiviral therapy for the treatment of this pandemic virus 1. It is also notable that many patients with COVID-19 had multiple comorbidities and are vulnerable to polypharmacy2,3 which may in turn leads to DDIs due to taking multiple medications. A recent clinical trial of LPV/RTV didn’t find superiority of using this combination in COVID-19 patients4. Although many factors e.g. age, sex, comorbidities, clinical features etc. might trigger the clinical outcomes, however, one of the major contributing factors of these may be partly due to the DDIs associated with COVID-19 patients due to having multiple comorbidities.
Being potent inhibitors of CYP3A4 enzyme, LPV/RTV can exert uniquely powerful inhibiting effects of CYP3A4 substrate drugs, potentially increased blood concentrations of substrate drugs which may leads to a number of clinically significant DDIs 5,6. Contrastingly, CYP3A4 inducer drugs may expedite the hepatic clearance of LPV/RTV and may cause therapeutic failure leading to reduced virologic control 7. Being acting as substrates of a transporter protein called permeability glycoprotein (P-gp)8 known as efflux transporter, the pharmacokinetics (PK) effects of LPV/RTV may also be affected by the co-prescription with substrate, inhibitor or inducer drugs of P-gp and were predicted to cause potential clinically significant DDIs.
However, the FDA prescribing information of LPV/RTV indicated that this combination therapy is ‘contraindicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions’. Also, it is ‘contraindicated with drugs that are potent CYP3A4 inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance’9.
On the other hand, the Liverpool interactions group has provided prescribing resources where they categorized the interactions of experimental COVID-19 antiviral therapies as ‘contraindicated medications’, ‘potential interactions requiring dose adjustment/close monitoring’, ‘potential interactions of weak intensity’ or ‘no clinically significant interactions 10. Contraindicated medications should not be coadministered concurrently due to potential life-threatening ADRs.
Amid this emergency situations, details of the treatments provided in COVID-19 patients and consequent clinical outcomes were not available and was therefore unable to assess either the actual ADRs/drug toxicity or potential clinically significant DDIs. It is also pertinent to noted that while in many countries especially in developed countries, DDI alert systems are functional, however, one of the major problems of implementing DDIs assessment in clinical practice is that most clinicians become fatigue to DDI alerts and majority of the time the alerts are overridden due to too much warnings 11.
Therefore, the present study was aimed to predictively identify severe DDIs pairs only predicted to cause life-threatening ADRs from international resources so as to aware clinicians regarding the severity of these interactions.