The authors included 92 patients in their study. Professor Parham Sendi, who is the co-leader of this study summarizes the main findings as follows: First, lopinavir plasma levels were more than two to threefold higher than typically observed in HIV patients. Hydroxychloroquine levels were with normal range. Second, there was a significant correlation between the inflammation marker levels in the blood and lopinavir plasma levels. Third, when the inflammation was blocked with the Interleukin-6 inhibitor Tocilizumab, lopinavir plasma levels were significantly lower than the ones in patients without Tozulizumab treatment.
These results clearly indicate that drug metabolism enzymes (cytochrome P450 3A) are inhibited by systemic inflammation. “Caution is advised when prescribing CYP3A4 substrates such as Lopinavir/ritonavir or any other drug with a narrow therapeutic index to Covid-19 patients because of the risk of elevated drug levels and related toxicities,” the authors state.
Importantly, from the lopinavir and hydroxychloroquine concentrations in the plasma, the study group calculated the corresponding concentration in the lung compartment – the anatomic site of SARS-CoV-2 infection. The results strongly suggest that it is unlikely that both drugs reach sufficient concentrations to inhibit the virus replication in the lung.
WHO accepted the recommendation from the Solidarity Trial’s International Steering Committee to discontinue the trial’s hydroxychloroquine and lopinavir/ritonavir arms on 4 July 2020. Professor Manuel Battegay – co-leader of this study and head of the Division of Infectious Diseases and Hospital Epidemiology at the University Hospital in Basel – mentioned that the results provide important pharmacological and antiviral insights to the rationale of discontinuing the lopinavir/ritonavir arm. In fact, they explain why hydroxychloroquine and lopinavir are not effective against the SARS-CoV-2.