Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly

Antimicrob Agents Chemother

Stoeckle

et al. 2020

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Background: Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP). Methods: LPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. Results: The median age of study participants was 59 (range 24–85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4–10) and 8 days (IQR 5–10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/mL (IQR 18.9–31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p<0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values. Conclusions: High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.

Section: Discussionmentioning

confidence: 99%

“…Because age-related physiological changes can affect drug pharmacokinetics ( 22 ), we categorized patients as <65 or ≥ 65 years old. As indicated earlier, we used a tentative CRP cutoff value of 75 mg/liter to aid decision-making for the administration of TCZ.…”

Section: Methodsmentioning

confidence: 99%

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Marzolini

Antimicrob Agents Chemother

Stoeckle

et al. 2020

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“…Secondly, the verified PBPK model predicted HIV drug pharmacokinetics across adulthood (20–99 years) to investigate the continuous effect of ageing. Results were compared to our study for non‐HIV drugs to support the overall care beyond HIV 9 . Thirdly, the general impact of ethnicity on age‐related changes of drug pharmacokinetics was analysed.…”

Section: Methodsmentioning

confidence: 99%

“…The slopes of the age‐related pharmacokinetic changes between men and women were statistically compared by a t ‐test for each investigated drug and pharmacokinetic parameter. All results were compared to our previous analysis for non‐HIV drugs 9 . Results are given as mean [95% confidence interval].…”

Section: Methodsmentioning

confidence: 99%

Effect of ageing on antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation

Courlet

Kinvig

et al. 2020

Brit J Clinical Pharma

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Aims The impact of ageing on antiretroviral pharmacokinetics remains uncertain, leading to missing dosing recommendations for elderly people living with human immunodeficiency virus (HIV: PLWH). The objective of this study was to investigate whether ageing leads to clinically relevant pharmacokinetic changes of antiretrovirals that would support a dose adjustment based on the age of the treated PLWH. Methods Plasma concentrations for 10 first‐line antiretrovirals were obtained in PLWH ≥55 years, participating in the Swiss HIV Cohort Study, and used to proof the predictive performance of our physiologically based pharmacokinetic (PBPK) model. The verified PBPK model predicted the continuous effect of ageing on HIV drug pharmacokinetics across adulthood (20–99 years). The impact of ethnicity on age‐related pharmacokinetic changes between whites and other races was statistically analysed. Results Clinically observed concentration–time profiles of all investigated antiretrovirals were generally within the 95% confidence interval of the PBPK simulations, demonstrating the predictive power of the modelling approach used. The predicted decline in drug clearance drove age‐related pharmacokinetic changes of antiretrovirals, resulting in a maximal 70% [95% confidence interval: 40%, 120%] increase in antiretrovirals exposure across adulthood. Peak concentration, time to peak concentration and apparent volume of distribution were predicted to be unaltered by ageing. There was no statistically significant difference of age‐related pharmacokinetic changes between studied ethnicities. Conclusion Dose adjustment for antiretrovirals based on the age of male and female PLWH is a priori not necessary in the absence of severe comorbidities considering the large safety margin of the current first‐line HIV treatments.

“…Furthermore, body composition changes with advanced ageing, towards more adipose tissue weight and lower body water, which does, however, not affect the volume of distribution. 5,6 In each age group, 100 subjects (50% women) in 10 trials were simulated. The reduction in DDI magnitude for midazolam was calculated using the last day of lopinavir/ritonavir administration as a basis.…”

mentioning

confidence: 99%

Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interacting effect

Journal of Antimicrobial Chemotherapy

Khoo

Stoeckle

et al. 2020

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Sir, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly infectious, causing coronavirus infectious disease 2019 (COVID-19) worldwide. 1 One of the experimental treatments includes the HIV drug lopinavir boosted with ritonavir. Both PIs cause irreversible mechanism-based inhibition (loss of metabolizing enzymes) and induction of metabolizing enzymes in the liver and intestine, which often leads to drug-drug interactions (DDIs) with co-medications. 2 The duration of cytochrome P-450 (CYP) 3A inhibition after stopping lopinavir/ritonavir treatment is not well understood, leading to some uncertainty as to how long to maintain adjusted doses of co-medications or when to restart drug therapies against comorbidities. We investigated the duration of hepatic and intestinal CYP3A inhibition after stopping lopinavir/ritonavir treatment by a verified modelling approach. 3 Lopinavir/ritonavir (400/100 mg twice daily) was administered for 7 days in a virtual trial to achieve steadystate CYP3A inhibition and the abundance of CYP3A was estimated for 21 consecutive days. The interaction potential after stopping lopinavir/ritonavir was investigated with the CYP3A probe substrate midazolam. Midazolam was administered orally (5 mg once daily) starting on the seventh day of the study. Simulations were performed in the four age categories 20 to 50 years, 60 to 69 years, 70 to 79 years and 80 to 89 years, because severe COVID-19 outcome is more likely in older individuals having comorbidities. 4 Our model takes age-related physiological changes into account. 3 These include a decrease in hepatic and renal blood flow and glomerular filtration rate, which lead to a decline in drug clearance.