. 2022 Sep 5;61(11):1519–1544. doi: 10.1007/s40262-022-01173-8

Table 2.

Physiologically based pharmacokinetic models investigating the effects of cytokine modulation on the pharmacokinetics of CYP substrates

Study, year of publication	Study population and design (N of included patients)	Drug and dosage	Inflammatory conditions and biomarker levels	Mechanism	Pharmacokinetic effect	Pharmacodynamic effect	Clinical relevance
Machavaram et al., 2013 [21]	Physiologically based pharmacokinetic model: patients with rheumatoid arthritis (12) or requiring a bone marrow transplant (5)	Simvastatin 40 mg (probe for 3A4) and cyclosporine 1.5 mg/kg (3A4)	Rheumatoid arthritis or bone marrow transplant Assessment of serum IL-6 levels	Downregulation of CYP3A4 metabolism mediated by increase in IL-6 levels	Elevated simvastatin AUC in virtual patients with rheumatoid arthritis, following 100 pg/mL of IL-6 was comparable to observed clinical data (59% vs 58%) In virtual patients requiring a bone marrow transplant, 500 pg/ml of IL-6 resulted in increase in cyclosporine AUC that was in good agreement with the observed data (45% vs 39%)	Not assessed	The application of physiologically based PK models is suitable for the prediction of drug–disease interactions via suppression of CYP by elevated levels of IL-6 in patients with rheumatoid arthritis or requiring a bone marrow transplant
Xu et al., 2015 [23]	Physiologically based pharmacokinetic model: virtual patients with non-Hodgkin lymphoma receiving blinatumomab	CYP probe drug cocktail: simvastatin (3A4), midazolam (3A4), theophylline (1A2), caffeine (1A2), warfarin (2C9)	Non-Hodgkin lymphoma Assessment of IL-6 and IL-10 serum levels	Downregulation of CYP metabolism mediated by transient increase in pro-inflammatory cytokines due to blinatumomab administration	Maximal suppression of transient IL-6 on CYP isoenzymes: 3A4: 28%, occurred at 48 h, lasted for 7 days 1A2: 9%, occurred at 48 h, lasted for 7 days 2C9: 17%, occurred at 70 h, lasted for 9 days Mean AUC (95% CI) ratio (transient IL-6 increase vs baseline) Simvastatin 1.9 (1.8–2.0) Midazolam 1.7 (1.6–1.8) Theophylline 1.1 (1.0–1.1) Caffeine 1.2 (1.1–1.3) Warfarin 1.2 (1.0–1.4) Mean C_max (95% CI) ratio (transient IL-6 increase vs baseline) Simvastatin 1.7 (1.6–1.8) Midazolam 1.2 (1.1–1.3) Theophylline 1.0 (1.0–1.0) Caffeine 1.0 (1.0–1.1) Warfarin 1.0 (1.0–1.0)	Not assessed	The magnitude of the suppressive effect of transient cytokine elevation on hepatic CYP enzyme activities is <30% for up to a week. Changes in exposures to substrates of CYP3A4, CYP1A2, and CYP2C9 are expected to be lower than two-fold and the magnitude of CYP suppression is highly dependent on the duration of cytokine elevation
Machavaram et al., 2019 [22]	Physiologically based pharmacokinetic model: virtual patients with neuromyelitis optica or neuromyelitis optica spectrum disorders in North European Caucasian, Japanese, or Chinese populations	CYP probe drug cocktail: caffeine 100 mg (1A2), warfarin 5 mg (2C9), omeprazole 20 mg (2C19), dextromethorphan 30 mg (2D6), midazolam 0.03 mg/kg (3A4), or simvastatin 40 mg (3A4)	Neuromyelitis optica or neuromyelitis optica spectrum disorders Assessment of IL-6 serum levels according to a previous study performed in patients with rheumatoid arthritis	Downregulation of CYP metabolism mediated by increase in IL-6 levels	Mean fold change in AUC (steady-state IL-6 levels from 10 to 100 pg/mL): Simvastatin AUC ↑ 2.36-fold Midazolam AUC ↑ 2.08-fold Omeprazole AUC ↑ 1.97-fold Dextromethorphan AUC ↑ 1.37-fold Warfarin AUC ↑ 1.29-fold Caffeine AUC ↑ 1.07-fold	Not assessed	Increasing levels of IL-6 led to predicted increases in exposure to the CYP probe substrates tested, with the exception of caffeine (CYP1A2), being the CYP3A4 substrates the most sensitive to IL-6-mediated suppression There were no notable ethnic differences between the North European Caucasian, Japanese, and Chinese populations in the sensitivity of the change in pharmacokinetics of CYP probe substrates following IL-6-mediated suppression

Study, year of publication

Study population and design (N of included patients)

Drug and dosage

Inflammatory conditions and biomarker levels

Mechanism

Pharmacokinetic effect

Pharmacodynamic effect

Clinical relevance

Machavaram et al., 2013 [21]

Physiologically based pharmacokinetic model: patients with rheumatoid arthritis (12) or requiring a bone marrow transplant (5)

Simvastatin 40 mg (probe for 3A4) and cyclosporine 1.5 mg/kg (3A4)

Rheumatoid arthritis or bone marrow transplant

Assessment of serum IL-6 levels

Downregulation of CYP3A4 metabolism mediated by increase in IL-6 levels

Elevated simvastatin AUC in virtual patients with rheumatoid arthritis, following 100 pg/mL of IL-6 was comparable to observed clinical data (59% vs 58%)

In virtual patients requiring a bone marrow transplant, 500 pg/ml of IL-6 resulted in increase in cyclosporine AUC that was in good agreement with the observed data (45% vs 39%)

Not assessed

The application of physiologically based PK models is suitable for the prediction of drug–disease interactions via suppression of CYP by elevated levels of IL-6 in patients with rheumatoid arthritis or requiring a bone marrow transplant

Xu et al., 2015 [23]

Physiologically based pharmacokinetic model: virtual patients with non-Hodgkin lymphoma receiving blinatumomab

CYP probe drug cocktail: simvastatin (3A4), midazolam (3A4), theophylline (1A2), caffeine (1A2), warfarin (2C9)

Non-Hodgkin lymphoma

Assessment of IL-6 and IL-10 serum levels

Downregulation of CYP metabolism mediated by transient increase in pro-inflammatory cytokines due to blinatumomab administration

Maximal suppression of transient IL-6 on CYP isoenzymes:

3A4: 28%, occurred at 48 h, lasted for 7 days

1A2: 9%, occurred at 48 h, lasted for 7 days

2C9: 17%, occurred at 70 h, lasted for 9 days

Mean AUC (95% CI) ratio

(transient IL-6 increase vs baseline)

Simvastatin 1.9 (1.8–2.0)

Midazolam 1.7 (1.6–1.8)

Theophylline 1.1 (1.0–1.1)

Caffeine 1.2 (1.1–1.3)

Warfarin 1.2 (1.0–1.4)

Mean C_max (95% CI) ratio

(transient IL-6 increase vs baseline)

Simvastatin 1.7 (1.6–1.8)

Midazolam 1.2 (1.1–1.3)

Theophylline 1.0 (1.0–1.0)

Caffeine 1.0 (1.0–1.1)

Warfarin 1.0 (1.0–1.0)

Not assessed

The magnitude of the suppressive effect of transient cytokine elevation on hepatic CYP enzyme activities is <30% for up to a week. Changes in exposures to substrates of CYP3A4, CYP1A2, and CYP2C9 are expected to be lower than two-fold and the magnitude of CYP suppression is highly dependent on the duration of cytokine elevation

Machavaram et al., 2019 [22]

Physiologically based pharmacokinetic model: virtual patients with neuromyelitis optica or neuromyelitis optica spectrum disorders in North European Caucasian, Japanese, or Chinese populations

CYP probe drug cocktail: caffeine 100 mg (1A2), warfarin 5 mg (2C9), omeprazole 20 mg (2C19), dextromethorphan 30 mg (2D6), midazolam 0.03 mg/kg (3A4), or simvastatin 40 mg (3A4)

Neuromyelitis optica or neuromyelitis optica spectrum disorders

Assessment of IL-6 serum levels according to a previous study performed in patients with rheumatoid arthritis

Downregulation of CYP metabolism mediated by increase in IL-6 levels

Mean fold change in AUC (steady-state IL-6 levels from 10 to 100 pg/mL):

Simvastatin AUC ↑ 2.36-fold

Midazolam AUC ↑ 2.08-fold

Omeprazole AUC ↑ 1.97-fold

Dextromethorphan AUC ↑ 1.37-fold

Warfarin AUC ↑ 1.29-fold

Caffeine AUC ↑ 1.07-fold

Not assessed

Increasing levels of IL-6 led to predicted increases in exposure to the CYP probe substrates tested, with the exception of caffeine (CYP1A2), being the CYP3A4 substrates the most sensitive to IL-6-mediated suppression

There were no notable ethnic differences between the North European Caucasian, Japanese, and Chinese populations in the sensitivity of the change in pharmacokinetics of CYP probe substrates following IL-6-mediated suppression

AUC area under concentration–time curve, C concentration, CI confidence interval, C_max peak concentration, CYP cytochrome P450, IL interleukin, PK pharmacokinetic, ↑ increased