Table 3.
Studies evaluating the impact of acute inflammatory episodes on the pharmacokinetics of drugs that are candidates for therapeutic drug monitoring
| Pharmacological class and drug | Mains enzyme (transporter) involved | Study type | Patients number (plasma/blood samples) | Population study (country) | Duration of the phenoconversion | Concentration of inflammatory biomarkers | Pharmacokinetic consequences | Clinical consequences | References |
|---|---|---|---|---|---|---|---|---|---|
| Antipsychotics | |||||||||
| clozapine | CYP1A2 | prospective observational study |
14 (70) | Schizophrenic patients with influenza vaccination (Finland) |
na | No difference in CRP after vaccination | No difference in [clozapine] and [metabolites] after vaccination. | na | (Raaska, Raitasuo, & Neuvonen, 2001) |
| clozapine | CYP1A2 | retrospective comparative study | 63 (63) (36 with therapeutic [clozapine]* and 27 with [clozapine] > 800 ng/mL) |
Heterogeneous psychiatric patients (Germany) |
na | CRP: 0.69 ±1.42 mg/L (therapeutic [clozapine]); 3.64 ± 6.13 mg/L ([clozapine] > 800 ng/mL) | Higher frequencies of increased CRP (> 5 mg/L) in patient with elevated [clozapine] | na | (Pfuhlmann et al., 2009) |
| clozapine | CYP1A2 | retrospective comparative study | 33 (116): CRP ≥ 5 mg/L | Heterogeneous psychiatric patients (Germany) |
na | CRP: 19.0 [range: 5.1-242.0] (≥ 5 mg/L group); 3.5 [range: 0.5-4.7] mg/L (< 5 mg/L group) |
Increased C/D and decreased norclozapine/clozapine metabolic ratio in patients with CRP ≥ 5 mg/L | na | (Hefner et al., 2016) |
| clozapine | CYP1A2 | retrospective observational study | 16 corresponding to 18 episodes of inflammation /infection (46) |
Schizophrenic patients with inflammation /infection (China) |
na | na | Increased C/D in 16/18 episodes. Reducing the clozapine dose to the half would be advisable in 11 episodes and to one-third in 5 episodes. |
na | (Ruan, Zang, Cheng, Wang, & de Leon, 2020) |
| clozapine | CYP1A2 | case report | 2 | Schizoaffective disorder patient with dermatitis and pulmonary infection (China) |
about 4-5 days | na | Increased C/D, [clozapine] and [norclozapine] during infection | na | (Ruan et al., 2018) |
| clozapine | CYP1A2 | case report | 4 | Psychiatric patients (Netherlands) |
na | CRP: 116 mg/L na na na |
[clozapine]* (dose): 1012 ng/ml (600 mg) 1824 ng/mL (400 mg) 2349 ng/mL (500 mg) 915 ng/mL (500 mg) |
Clinical deterioration, loss of appetite, vomiting, somnolence | (Haack et al., 2003) |
| clozapine | CYP1A2 | case report | 1 | Adult schizophrenic with severe respiratory infection (USA) |
na | na | [clozapine]* (dose): 1245 ng/mL (600 mg) |
Sedation and problems walking | (de Leon & Diaz, 2003) |
| clozapine | CYP1A2 | case report | 1 | Adult with maniac and paranoid syndrome and urinary infection (Germany) |
na | CRP at day 13: 81.5 mg/L | [clozapine]* (dose) at day 17: 1006 ng/mL (200 mg) |
na | (Jecel et al., 2005) |
| clozapine | CYP1A2 | case report | 1 | Adult with schizophrenia, Crohn disease and admitted for a suspected gastrointestinal infection | na | CRP at admission: 130 mg/L | [clozapine]* (dose) - 1 month before admission: 627.1 ng/mL (900 mg) - At admission: 2965.4 ng/ml (900mg) |
na | (Espnes, Heimdal, & Spigset, 2012) |
| risperidone | CYP2D6 |
case report | 2 | Adult psychiatric patients (Germany) | about 2 days | CRP range: 0.8 to 110.0 mg/L | Simultaneous evolution of CRP and C/D during the follow-up of 16 and 5 days | na | (Hefner, Falter et al 2015) |
| risperidone | CYP2D6 |
retrospective comparative study | 32 (102): CRP > 5 mg/L | Heterogeneous psychiatric patients (Germany) |
na | CRP: 11.0 [range: 5.6-110.0] (> 5 mg/L group); 2.7 [range: 0.0-4.8] mg/L (< 5 mg/L group) |
Increased risperidone +OH-risperidone C/D in patients with CRP ≥ 5 mg/L No difference in risperidone/OH-risperidone metabolic ratio between 2 groups |
na | (Hefner et al., 2016) |
| risperidone | CYP2D6 | case report | 1 | 56-year-old men with schizophrenia and atypical pneumonia | na | CRP : 30.0 mg/L | Increased risperidone + OH-risperidone concentration to 405 nmol/L 1 week after admission (therapeutic range 50-140 nmol/L). | no adverse effect was observed | (Helland et al., 2018) |
| quetiapine | CYP3A4 |
retrospective comparative study | 40 (101): CRP > 5 mg/L | Heterogeneous Psychiatric patients (Germany) |
na | CRP: 1.5 [range : 5.3-116.0] (> 5 mg/L group): 2.8 [range : 0.2-4.5] mg/L (< 5 mg/L group) |
No difference in norquetiapine/quetiapine metabolic ratio or quetiapine C/D between the 2 groups | na | (Hefner et al., 2016) |
| Antidepressants | |||||||||
| citalopram | CYP2C19 | retrospective comparative study | 30 (30) (15 with CRP > 5 mg/L and 15 with CRP < 5mg/L) | Heterogeneous psychiatric patients (Germany) |
na | CRP: 13 [range :5.2-37.0] (> 5 mg/L group); 2.0 [range :0.5-4.7] mg/L (< 5 mg/L group) |
No difference in C/D and metabolic ratio between the 2 groups | na | (Hefner, Shams, et al., 2015) |
| venlafaxine | CYP2C19 CYP2D6 |
retrospective comparative study | 78 (78) (39 with CRP > 5 mg/L and 39 with CRP < 5mg/L) | Heterogeneous psychiatric patients (Germany) |
na | In CRP: 11 [range: 5.3-232.0] (> 5 mg/L group); 3.2 [range: 0.0-4.8 mg/L] mg/L (< 5 mg/L) | No difference in C/D and metabolic ratio between the 2 groups | na | (Hefner et al., 2016) |
| Antiepileptics | |||||||||
| perampanel | CYP3A4 | retrospective comparative study | 111 (111) (23 with CRP > 15 mg/L and 88 with CRP <15mg/L) | Heterogeneous epileptic patients (Japan) |
C/D ratio returned to baseline within 1 week after normalization of CRP (case presentation of one pediatric patient) | In CRP > 15 mg/L group: 42 mg/L [range : 15-102 mg/L] |
Increased C/D ratio in patients with CRP > 15 mg/L both in the presence and absence of comedication with enzyme-inducing antiepileptics | No adverse events were recorded | (Yamamoto et al., 2018) |
| clobazam | CYP3A4 | case report | 1 | Child with Rett syndrome and pneumonia (Japan) | na | na | No change in [clobazam] or [N-desmethylclobazam] during the study period of 77 days |
No adverse events were observed | (Yamamoto et al., 2018) |
| Sedative drugs | |||||||||
| midazolam | CYP3A4 |
external evaluation of a previously developed PK model (Vet et al., 2016) | 136 (1045) | Neonates, infants, children and adults (Netherlands) |
na | CRP: 0.1 to 341 mg/L | MPE <30% for predicted CL in postoperative or critically ill patients and term neonates, critically ill and healthy adults. MPE > 180% in preterm neonates |
na | (Brussee et al., 2018) |
| midazolam | CYP3A4 |
prospective observational study (PK analysis) |
83 (523) | Critically ill children (Netherlands) |
na | In simulations, CRP of 300 mg/L was associated with 65% lower clearance compared to 10 mg/L | Association between CL and: - CRP - organ failure No association between CL and IL-6 and TNFα levels |
na | (Vet et al., 2016) |
| midazolam | CYP3A4 |
prospective observational study (PK analysis) |
45 (192) | Terminally ill adult patients (Netherlands, 91.1% Caucasian) | na | CRP: 92 [range: 1-625] mg/L | Correlation between CL and albumin or CRP (depending on the order on the backwards elimination in covariates selection) | na | (Franken et al., 2017) |
| midazolam | CYP3A4 |
prospective observational study (PK analysis) |
21 (na) | Critically ill children (Netherlands) |
na | na | No association between CL and inflammatory markers (CRP and leucocytes count). Correlation between CL and disease severity |
na | (Vet et al., 2012) |
| Immunosuppressant drugs (mTOR inhibitor) | |||||||||
| sirolimus | CYP3A4/5 (Pgp) |
prospective observational study (PK analysis) | 52 (676) | Children with vascular anomalies (USA) |
na | na | Drop of about 50% of CL during documented infection | na | (Mizuno et al., 2017) |
| sirolimus | CYP3A4/5 (Pgp) |
Case report | 2 | Children with acute lymphoblastic leukemia (USA) | At least 2 days | na | High Cmin when patients had flu-like symptoms (fever and cough) | Toxicity events (seizure and mouth sore) | (Mizuno et al., 2019) |
| Immunosuppressant drugs (antiproliferative drug) | |||||||||
| mycophenolate sodium (enteric-coated) | UGT1A8/9 | prospective observational study (PK analysis) | 66 (666) | Kidney transplant adults (Germany) | na | na | Higher AUC0–12h in patients with recurrent infections compared to patients without infections | na | (Sommerer et al., 2010) |
| mycophenolate mofetil | UGT1A8/9 | prospective observational study (PK analysis) |
46 (127)(15 with infection or gastrointestinal disease and 31 without) | Kidney transplant adults (Japan) | na | na | A trend towards higher AUC0-9h in patients with infection or gastrointestinal disease compared to those without | na | (Okamoto et al., 2005) |
| Immunosuppressant drugs (calcineurin inhibitor) | |||||||||
| tacrolimus | CYP3A4/5 (Pgp) |
prospective observational study (PK analysis) | 30 (200) (11 with diarrhea and 9 controls) |
Kidney transplant adult (Belgium) | na | na | Association between diarrhea and Cmin Increase of C/D between 90 and 360 min after intake. No change of Tmax and t1/2 Decrease by about 50% (± 50%) of intestinal Pgp activity during diarrhea |
na | (Lemahieu et al., 2005) |
| tacrolimus | CYP3A4/5 (Pgp) |
prospective observational study (PK analysis) | 20 (na) | Kidney transplant adults (Japan) | from 2 to 4 weeks | na | Higher Cmin, AUC, and Cmax during episodes of diarrhea | na | (Sato et al., 2004) |
| tacrolimus | CYP3A4/5 (Pgp) |
case report | 2 (23) | Liver transplant adults (Japan) | from 2 to 4 weeks | na | Decrease of Cmin two weeks after 2 or 4 weeks of direct-acting antivirals administration for HCV infection | Dose increase adjustment between 25% and 50 % | (Smolders et al., 2017) |
| tacrolimus | CYP3A4/5 (Pgp) |
case report | 1 (13) | Liver transplant child (Japan) | na | na | Increase of Cmin by 100% after an episode of diarrhea with fever | na | (Maezono et al., 2005) |
| tacrolimus | CYP3A4/5 (Pgp) |
case report | 2 (7) | Liver transplant adults |
na | CRP range: 70 to 236 mg/L | Increase of Cmin Increase of C/D by 92 to 141% after inflammatory events |
na | (Bonneville et al., 2020) |
| cyclosporine | CYP3A4/5 (Pgp) |
retrospective observational study | 6 (88) | Adult recipients of allogeneic stem cell transplant (France) | na | Peak IL-6 : 212.2 ± 56.8 UI/ml Peak CRP: 179.2 ± 12.5 mg/L Peak α1-acid glycoprotein : 2.59 ± 0.32 gm/L |
Correlation between time of IL-6 peak and: -three-fold increase in blood [cyclosporine] -twofold increase in [AM1**] |
Cyclosporine dose decrease between 25 and 50% | (Chen et al., 1994) |
| cyclosporine | CYP3A4/5 (Pgp) |
case report | 1 (10) | Liver transplant adult (Japan) | na | na | Increase of Cmin by 300% 24 hours after an episode of diarrhea with fever |
na | (Maezono et al., 2005) |
| Triazole antifungals | |||||||||
| voriconazole | CYP2C19, CYP3A4 | prospective observational study | 34 (489) | Adult hematological and SOT patients (Netherlands) |
na | Na | Increase of Cmin by 1.005321N and decrease of [voriconazole-N-oxide] by 0.99775N, with N being the difference in CRP units (expressed in mg/L) | na | (Veringa et al., 2017) |
| voriconazole | CYP2C19, CYP3A4 | prospective observational study | 22 (143) | Hematological adult (Netherlands) |
na | CRP: 37 [12 - 75] mg/L IFNɣ: 15 [10-29] pg/mL IL10: 35 [12-66] pg/mL IL1-RA: 34 [18-106] pg/mL IL1ß: 9.5 [8.5–11] pg/mL IL6: 32 [12-80] pg/mL IL8: 54 [22-122] pg/mL TNFα: 26 [15-44] pg/mL |
Independent association between Cmin and CRP, IL-6, and IL-8. Absence of association between Cmin and other cytokines |
na | (Vreugdenhil et al., 2018) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 67 (520) | Adult recipients of allogeneic stem cell transplant (Japan) |
na | CRP: 32 [range: 1–200.1] mg/L | CRP ⩾ 4 mg/L identified as an independent factor of Cmin ⩾1 mg/L | na | (Yasu et al., 2017) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 29 (260) | Adult recipients of allogeneic stem cell transplant (France) |
na | CRP: 8 [3-24] mg/L | Independent positive association between Cmin and CRP Increase of 24% of Cmin for each 1-log decimal increase of CRP |
na | (Gautier-Veyret et al., 2017) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 113 (250) | Hematological adult (China) |
na | CRP: 5.99 (range:3-171) mg/L IL1ß: 0.03 (< 0.1-489.3) pg/mL IL6: 135.1 (1.98-2969.1) pg/mL IL18: 141.9 (5.7-1834.7) pg/mL TGFß1: 1750.9 (37.5-37916) pg/mL IFNɣ: 0.23 (< 0.3-24.5) pg/mL |
Absence of association between Cmin and CRP Association between Cmin and:
|
na | (Mafuru et al., 2019) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 50 (139) | Adult hematological and SOT patients (Netherlands) |
na | CRP:67 [14-153] mg/L | Association between Cmin and CRP Simultaneous evolution of Cmin and CRP level at individual level |
na | (Encalada Ventura et al., 2016) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 128 (128) | Adult hematological and SOT patients (Netherlands) |
na | CRP: 71 [15–152] mg/L | Independent positive association between CRP and Cmin For every 1-mg/L increase in the CRP, increase of 0.015 (CI 95%: 0.011-0.020) mg/L of Cmin. Simultaneous evolution of Cmin and CRP at individual level |
na | (Van Wanrooy et al., 2014) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 19 (101) | Adult hematological and SOT patients (Netherlands) |
na | CRP: 76.6 (range: 5.0–279.0) mg/L | Correlation between CRP and: - Cmin - metabolic ratio Increase of 0.021 mg/L for Cmin for each increase of 1 mg/L of CRP |
na | (Encalada Ventura et al., 2015) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 63 (77) | Adult hematological and SOT patients (Japan) |
na | CRP: 5.6 ±6.4 mg/L | Increased CRP identified as an independent predictor of C/D | na | (Dote et al., 2016) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 65 (72) | na (Japan) |
na | na | Independent association between CRP and: - first Cmin - metabolic ratio |
na | (Niioka et al., 2017) |
| voriconazole | CYP2C19, CYP3A4 | retrospective observational study | 41 (41) | Heterogeneous immunocompromised patients (Japan) | na | CRP: 3.46 [1.36–7.57] mg/L | Correlation between CRP : - Cmin/D - metabolic ratio |
na | (Naito et al., 2015) |
| voriconazole | CYP2C19, CYP3A4 | case-control study | 62 (62) (31 cases with Cmin ≥ 4 mg/L** and 31 controls) | Hematological adults (France) |
na | CRP:188 [109–227.5] (case); 37 [13.2–83.0] mg/L (control) | Class of CRP (> 96mg/L) identified as the unique independent factor of overexposure** | na | (Gautier-Veyret et al., 2019) |
| voriconazole | CYP2C19 CYP3A4 FMO3 |
retrospective comparative study | 27 children (11 < 12 years and 16 > 12 years) | Na (Netherlands) |
na | na | Positive association between CRP and Cmin in child >12 years No association between CRP and Cmin in children < 12 years |
na | (ter Avest et al., 2017) |
| voriconazole | CYP2C19, CYP3A4 | case report | 1 (11) | Hematological adult (France) |
na | CRP range: 25 to 263 mg/L | Simultaneous evolution of CRP and Cmin during the follow-up of 60 days | na | (Truffot et al., 2018) |
| posaconazole | UGT1A4 | prospective observational study | 55 (511) | Hematological adult (Netherlands) |
na | CRP: 23.5 [5-75] mg/L | No association between CRP and Cmin | na | (Märtson et al., 2019) |
| itraconazole | CYP3A4/5 | retrospective observational study | 42 (42) | Heterogeneous immunocompromised patients (Japan) | na | CRP: 0.12 [0.04–0.66] mg/L | No association between CRP and: - C/D - hydroxyitraconazole - metabolic ratio |
na | (Naito et al., 2015) |
| Anti-asthmatic drugs | |||||||||
| theophylline | CYP1A2 | retrospective comparative study | 52 (na) | Children with asthma (Japan) | about 2 days | na | Increased incidence of CRP > 0.5mg/L or fever in patients with lower Cmin72 h/Cmin24 h compared to patients with higher Cmin72 h/Cmin24 h ratio | na | (Yamaguchi et al., 2000) |
| theophylline | CYP1A2 | case report | 11 (na) | Children with asthma (USA) |
between 1 to 3 months | na | Increased Cmin during influenza infection | toxic symptoms (seizure, nausea/vomiting, headache) in 10/11 patients | (Kraemer et al., 1982) |
| theophylline | CYP1A2 | case report | 5 (na) | Children with asthma (USA) | na | nd | Increased t1/2 during acute viral infection | na | (Chang et al., 1978) |
| theophylline | CYP1A2 | case report | 1 (na) | Adult healthy volunteer (Canada) | na | nd | Doubled t1/2 during acute viral infection | na | (Fleetham et al., 1978) |
| Anti-malaria drugs | |||||||||
| quinine | CYP3A4 | prospective study (PK analysis) | 5 (na) | Adults with experimentally-induced malaria (USA) | na | body temperature: 38.1± 0.2 °C | Increased exposure during experimentally-induced malaria | Symptoms of cinchonism during malaria | (Morgan et al., 2018; Trenholme, Williams, Rieckmann, Frischer, & Carson, 1976) |
| quinine | CYP3A4 | prospective study (PK analysis) | 73 (na) (51 infected patients and 22 controls) | Children with uncomplicated malaria (na) |
na | na | Reduced CL, Vd during malaria and increased exposure during uncomplicated malaria episode | No adverse effect was recorded | (Morgan et al., 2018; Sabchareon, Chongsuphajaisiddhi, & Attanath, 1982) |
| quinine | CYP3A4 | prospective comparative study (PK analysis) | 38 (na) (25 cerebral malaria and 13 uncomplicated malaria) | Adults and children with malaria (Thailand) | na | na | Reduced CL, Vd during malaria (especially in cerebral malaria) compared to convalescence period | No adverse effect was recorded | (Morgan et al., 2018; White et al., 1982) |
| quinine | CYP3A4 | prospective comparative study (PK analysis) | 15 (na) | Adults with malaria (Thailand) | less than 7 days | body temperature: 38.4 ±1.2°C Parasitemia: 58100 [18600-183000] parasites/μL |
Decreased CL and increased exposure during malaria episode compared to convalescence period | na | (Morgan et al., 2018; Supanaranond et al., 1991) |
| quinine | CYP3A4 | prospective study (PK analysis) | 16 (na) | Adult patients with severe or moderately severe malaria (Thailand) | na | body temperature: 38.4 [range: 37.0-40.1] °C parasitemia: 15054 [range: 44-346222] parasites/μL |
Reduced Cl, Vd during malaria episode compared to convalescence period | na | (Morgan et al., 2018; Pukrittayakamee et al., 1997) |
| quinine | CYP3A4 | prospective study (PK analysis) | 6 (na) | Adults and children with uncomplicated malaria (Nigeria) | na | body temperature: 38.6 ± 0.6°C parasitemia: 33064 [range: 11250-58999] parasites/μL |
Reduced CL, Vd and increased exposure during malaria episode compared to convalescence period | No adverse effect was recorded | (Babalola, Bolaji, Ogunbona, Sowunmi, & Walker, 1998; Morgan et al., 2018) |
| quinine | CYP3A4 | prospective study (PK analysis) | 22 (na) | Pregnant women (2nd and 3rd trimester) (Uganda) |
na | body temperature: 37.2 [36.0-38.9] °C parasitemia: 2240 [39.0-44.5] parasites/μL |
Body temperature and parasitemia identified as covariates affecting CL and bioavailability, respectively | No adverse effect was recorded | (Kloprogge et al., 2014; Morgan et al., 2018) |
| Anti-viral drugs | |||||||||
| lopinavir | CYP3A4 | retrospective observational study | 8 (8) | COVID-19 adult patients | nd | CRP range: 1.6 to 184.7 mg/L | Correlation between Cmin and CRP | na | (Schoergenhofer et al., 2020) |
| lopinavir | CYP3A4 | retrospective observational study | 12 (30) | COVID-19 adult patients | nd | CRP range: 19.4 to 157.5 mg/L |
High bound and unbound Cmin in COVID-19 patients compared to HIV patients | Diarrhea (n=6), nausea/vomiting (n=2) | (Gregoire et al., 2020) |
AM: cyclosporine metabolites, C/D: concentration/dose ratio, Cmin: trough concentrations, CL: clearance, Cmin: trough concentration, CRP: C reactive protein, CYP: cytochrome, FMO: flavin-monooxygenase 3, na: not available, nd: not determined, IL-6: interleukin 6, Pgp: glycoprotein P, PK: pharmacokinetics, MPE: median predicted error, t1/2: elimination half-life, SOT: solid organ transplant, Tmax: time after dose to maximum concentration, TNFα: tumor necrosis factor α, Vd: volume of distribution.
Data are indicated as mean (interval confidence or SD) or median [25th-75th percentile or range].
*Clozapine therapeutic reference range: 350-600 ng/mL (Hiemke et al., 2018); ** Voriconazole therapeutic reference range : 1-4 mg/L.