Drug
Mechanism
Effects
Severity
Comments
Anti-folate antibiotics
Additive depletion
Pancytopenia
2
Avoid, monitor MTX level
NSAIDs
Impaired MTX excretion
Renal toxicity
3
Avoid, monitor MTX level
Probenecid
Impaired MTX excretion
Increased MTX level
2
Monitor MTX level
Phenytoin
Displaced protein binding
Increased MTX level
3
Monitor MTX level
Renal impairment alters the pharmacokinetics of drugs and metabolites requiring drug dosing adjustments. Decreased clearance has been observed for drugs primarily eliminated by the kidney, but also by drugs eliminated by non-renal pathways [8–10]. Further research is necessary utilizing physiologically based pharmacokinetic modeling (PBPK) to explore these changes in renal impairment [11, 12]. Determination of clinical drug-dosing regimens should take potential pharmacokinetic changes into consideration.
The majority of patients with chronic renal disease (CKD) are elderly with multiple comorbidities such as dermatological disorders requiring systemic therapy which place them at high risk for drug-related problems [13–16]. Most of the research conducted on the development of new oral or topical drugs or effects of established drugs excludes older adults, especially those over 70 years old with skin disease and chronic kidney disease [17]. For this reason, there are many different approaches and not always an evidence-based foundation for the prescribing and monitoring of drugs for the population with CKD [18]. There are few absolute contraindications for use of drugs in CKD; however, for most drugs, dosage adjustment is required to avoid toxic accumulation of drug or metabolites [19].
Absorption
Most drugs are absorbed orally by passive diffusion [20]. The site of absorption will determine a drug’s absorption speed and amount. The speed and degree of distribution of a drug will determine the amount of drug available to exert pharmacological effects on the body and how much time it will take to eliminate the drug from the body. It is possible that the pH and blood flow of different absorption sites in the body, such as the skin, could be altered by the chronic renal failure and so affect the rate and extent of drug absorption and distribution of a particular agent. For example, compared to patients with normal renal function, absorption of a number of topical agents were reported to be reduced following topical administration, in particular hydrophilic compounds, in patients with CKD. Decreased microcirculation or alternation of skin structure in part may be involved in reduced drug absorption for percutaneous administration [21]. The reduced adipose layer of the skin has been shown to be associated with a decrease in the absorption of testosterone or hydrocortisone formulations.
Distribution
The effects of CKD on drug distribution are related to the degree of hypoalbuminemia exhibited by CKD patients experiencing malnutrition and increased albuminuria [22]. Alterations to albumin binding sites reduce affinity for acidic drugs and promote competition for albumin binding with organic acids that accumulate because of reduced renal excretion. Subsequently, protein binding of acidic drugs may be reduced in CKD. Toxicity may result with higher levels of unbound drug exerting its pharmacologic effect requiring frequent monitoring of blood levels. Maintaining lower levels of total drug or monitoring unbound drug is recommended for CKD. Drugs exhibiting decreased protein binding include theophylline, phenytoin, MTX, diazepam, prazosin, cephalosporins, penicillins, furosemide, and valproic acid [23]. In addition to changes in protein binding, pharmacodynamic properties such as activity and affinity of receptors, signal transduction, and hormonal regulation can be affected by chronic kidney disease [24].
Metabolism
Implications of CKD on pharmacokinetics also influences drug-dosing. First-pass drug metabolism and the enterohepatic cycle facilitate drug absorption and bioavailability, but these processes are disrupted in CKD [9]. Decreased intestinal cytochrome P450 (CYP) enzyme activity as well as limited protein and substrate expression is suggested to promote increased bioavailability of several oral drugs in renal failure patients. Most studies have expressed a reduction in expression of cytochrome P-450 enzymatic system in chronic kidney disease. Although there is very limited information, it seems kidney diseases and uremia may influence drug metabolism. Uremic proteins may alter the expression of messenger RNA (mRNA) of cytochrome P450 enzymes. Calcium and phosphate metabolism are disturbed in moderate to severe CKD. Calcium is commonly low-normal or low in renal failure. High parathyroid hormone (PTH) is a physiological response to low calcium, and to the phosphate retention that occurs in renal failure. During chronic kidney disease, PTH and PTH analogous have shown to reduce drug metabolism and downregulate expression of cytochrome P450 enzymes [25]. Cyclosporine, tacrolimus, propranolol, propoxyphene, human immunodeficiency virus (HIV) protease inhibitors, and immunosuppressive drug availability is increased during decreased intestinal metabolism [26]. In contrast, CKD also leads to decreased bioavailability of drugs as influenced by hepatic metabolism through increased release of uremic factors like PTH and inflammatory cytokines resulting in an alkalytic gastric environment. Medications such as antacids, phosphate binders, proton pump inhibitors, and histamine-receptor blockers enhance an elevated pH thus limiting the absorption of drugs requiring an acidic environment like furosemide and ferrous sulfate. Physical symptoms of edema, vomiting, and diarrhea also limit drug transit time in the intestines resulting in decreased drug absorption.
Renal Elimination
Renal impairment alters the pharmacokinetics of drugs and metabolites requiring drug dosing adjustments. Decreased clearance has been observed for drugs primarily eliminated by the kidney, but also by drugs eliminated by non-renal pathways [11, 12]. It is very important to avoid any drug with potential of nephrotoxicity to be avoided or discontinued temporarily or indefinitely (Table 20.2).
Table 20.2
Comparison of formulas estimating GFR for drug dosing
Formula name | Equation | Clinical considerations |
|---|---|---|
CGa | Creatinine clearance (mL/min) = (140 − age in years) × actual weight (kg)/serum creatinine (micromol/L); Multiply the result by 1.2 for men | • Estimates creatinine clearance not adjusting for BSA; • Standard for drug dosing despite limitations between pharmacokinetics and clinical practice |
MDRDa | Estimated GFR (mL/min/1.73 m2) = 186 × (SCr)−1.154 × (Age)−.203 ×(0.742 if female) × (1.210 if African American) = expanded (5.228 − 1.154 × In(SCr) − 0.203 × In(Age) − (0.299 if female) + (0.192 if African American) | • Estimates GFR adjusting for BSA; • Used for drug dosing despite limitations between pharmacokinetics and clinical practice; • Valid for specified racial groups (African Americans, Europeans, Asians), patients with diabetes, kidney transplant recipients, and potential kidney donors; • Less accurate in those without CKD; • Invalid in children, pregnant women, elderly, some races, nutritional status and muscle mass variation |
CKD-EPI | GFR = 141 × min(SCr/κ,1)α × max(SCr/κ,1)−1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black]; Where SCr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1 | • Estimates GFR adjusting for BSA; • Not recommended for drug dosing; • Valid with higher levels of GFR, young patients with type 1 diabetes, and kidney donation evaluation; • Accurate as MDRD equation in CKD patients having lower GFR levels; • Invalid in children, pregnant women, some races, nutritional status and muscle mass variation |
Determination of clinical drug-dosing regimens should ultimately be individualized and based upon kidney function as measured by GFR [19]. Since GFR cannot be measured directly, intrinsic markers such as inulin, iothalamate, or iohexol are the desired standard, but unrealistic for use in clinical practice due to a complicated measurement process and expensive laboratory cost [27]. Thus endogenous filtration markers, typically serum creatinine and urine measures, are used to estimate GFR [28, 29]. It is important to note serum creatinine alone is not an adequate representation of kidney function as the serum level is affected by multiple physiologic processes varying widely among individuals. For instance, older age, female sex, restriction of dietary protein, malnutrition, muscle wasting, and amputation decrease serum creatinine concentrations while African American race, ingesting cooked meats, and muscle mass increases levels. Estimates of GFR are achieved through recommended formulas that account for serum creatinine and other patient characteristics (age, sex, weight, or race). The Cockcroft-Gault (CG) equation [30], the Modification of Diet in Renal Disease (MDRD) [31], and the most recent, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [32] assist in identifying patients with CKD and screening for those at high-risk of disease development. Variations in GFR estimates exist among these valid equations and it is uncertain which formula provides the most accurate medication dosing recommendations; therefore clinical judgment must be applied appropriately per patient application. The CG equation and MDRD are recommended for determining clinical drug-dosing regimens in CKD despite equation limitations. See Table 20.3 for a comparison of formulas for estimating kidney function test.
Table 20.3
These agents must be avoided or to be used with caution in patients with chronic kidney disease
Class | Examples |
|---|---|
Antibiotics | Aminoglycosides vancomycin, sulfamethoxazole |
Antifungals | Amphotericin B |
Antivirals | Foscarnet, indinavir, cidofovir |
Anticoagulants | Low molecular weight heparins, warfarin |
Cardiac drugs | Digoxin, sotalol, ACE-I, ARB, DRIs |
Opioids | Morphine, meperidine, prophoxyphene |
Psychotropics/anticonvulsants | Amisulpride, gabapentin, lithium, levetiracetam, topiramate, vigabatrin |
Hypoglycaemic drugs | Metformin, glyburide, insulin |
Drugs for gout | Allopurinol, colchicine |
Others | Methotrexate, penicillamine, NSAIDs |
In fact, the most common drug dosing recommendations are based on pharmacokinetic studies that used creatinine clearance as estimated by the CG equation for a measure of kidney function. Now MDRD is most commonly used in the clinic setting to assess kidney health and stage CKD. However, healthcare professionals should proceed cautiously using these equations in special populations like geriatrics where use of a conservative estimate (CG equation) may be desired especially when prescribing drugs with a narrow therapeutic index in order to prevent toxicity and maximize efficacy [28].
Drug Dosing in Kidney Disease
Loading Dose
Loading doses are used when reaching therapeutic concentrations of medication promptly is necessary for adequate treatment of the patient. Steady state concentrations of medications in patients with normal renal function are reached after approximately five medications half-lives. Often, decreased dosing recommendations for patients with CKD prolongs the time it takes to reach steady-state. Loading doses may be particularly important in this population. Despite possible reductions in maintenance dosing regimens, loading dose recommendations remain consistent despite reductions in kidney function. A formula may be used to assist in calculating an appropriate loading dose [33].
![$$ \mathrm{L}\mathrm{D} = \mathrm{V}\mathrm{d}\times \left[\mathrm{C}\mathrm{p}\right] $$](/wp-content/uploads/2016/04/A306015_1_En_20_Chapter_Equa1.gif)
Vd = volume of distribution in l/kg of ideal body weight in kg and Cp is the desired concentration in the plasma in mg/L [34].
Maintenance Dose
As mentioned above, reductions in renal excretion necessitate dose adjustments for many medications, particularly those excreted unchanged in the urine. Consideration of renally eliminated active metabolites should be considered as well. Dose adjustments are primarily determined based on patient calculated GFR (see Table 20.3). Two primary strategies are used for drug adjustment in decreased renal function, dose reductions and increasing dosing interval. The ideal reduction strategy should be based on individual medication pharmacokinetic characteristics and goals of therapy [10]. Dose reductions allow for more constant drug levels within the body. However, the risk of drug accumulation is higher. Extension of dosing interval may be used for dose adjustment as well. Longer dosing intervals allows for the medication to reach adequate peak concentrations with increased duration between doses to allow for slowed clearance in kidney disease. Based on the extent of kidney disease, likely a combination of dosing reductions and extension of dosing interval are necessary for ideal plasma concentrations [35].
Patients with CKD requiring intermittent hemodialysis (IHD) necessitate further considerations when determining maintenance dose. Protein binding, volume of distribution, and molecular weight of the drug are some factors contributing to extent of drug removal during IHD. Drug removal is primarily through diffusion across the dialysis membrane. Highly protein bound medication will not be removed during dialysis as only free drug will be removed. In addition, medications with a large volume of distribution (>0.7 mL/kg) will have minimal removal due to widespread tissue binding. Molecular weight or size of the molecule passing the membrane influences its ability to be removed. Medications <500 Da are readily removed across dialysis membranes. Finally, frequency, duration and type of membrane may influence the extent of drug removal. Consideration can assist in determining maintenance dosing and potential need for supplemental doses post-dialysis to maintain consistent plasma concentrations [36].
Therapeutic Drug Monitoring
Therapeutic drug monitoring can be beneficial for medications with a narrow therapeutic index as dosage adjustments may not be sufficient to prevent toxicities in patients with CKD (Table 20.3). Despite the benefits, therapeutic drug monitoring is unavailable or expensive for many narrow therapeutic index medications. Medications used for dermatological disease such as tacrolimus, cyclosporine, MTX, and others have plasma concentration assays and are commonly monitored. In addition, these agents are at great risk for drug interactions (Tables 20.4, 20.5, 20.6, 20.7, and 20.8). These levels can assist in predicting both clinical response and potential for toxicity. However, it is important to consider the whole patient when utilizing plasma concentrations to dose medications as toxicity may occur despite therapeutic plasma concentrations. Concomitant nephrotoxic medications or competition for secretion can contribute to toxicity despite previously therapeutic plasma levels (Table 20.3). When medications such as these are added to a patient’s medication regimen or if fluctuations in renal function occur, therapeutic drug monitoring should be repeated.
Table 20.4
Therapeutic drug monitoring
Drug name | Therapeutic range | When to draw sample | How often to draw levels |
|---|---|---|---|
Aminoglycosides (conventional dosing) gentamicin, tobramycin, amikacin | Gentamicin and tobramycin: Trough: 0.5–2 mg/L Peak: 5–8 mg/L Amikacin: Peak: 20–30 mg/L Trough: < 10 mg/L | Trough: Immediately prior to dose Peak: 30 min after a 30–45 min infusion | Check peak and trough with third dose For therapy less than 72 h, levels not necessary. Repeat drug levels weekly or if renal function changes |
Aminoglycosides (24-h dosing) gentamicin, tobramycin, amikacin | 0.5–3 mg/L | Obtain random drug level 12 h after dose | After initial dose. Repeat drug level in 1 week or if renal function changes |
Carbamazepine | 4–12 mcg/mL | Trough: Immediately prior to dosing | Check 2–4 days after first dose or change in dose |
Cyclosporin | 150–400 ng/mL | Trough: Immediately prior to dosing | Daily for first week, then weekly |
Digoxin | 0.8–2.0 ng/mL | 12 h after maintenance dose | 5–7 days after first dose for patients with normal renal and hepatic function; 15–20 days in anephric patients |
Lidocaine | 1–5 mcg/mL | 8 h after i.v. infusion started or changed | |
Lithium | Acute: 0.8–1.2 mmol/L Chronic: 0.6–0.8 mmol/L | Trough: Before a.m. dose at least 12 h since last dose | |
Phenobarbital | 15–40 mcg/mL | Trough: Immediately prior to dosing | Check 2 weeks after first dose or change in dose. Follow-up level in 1–2 months. |
Phenytoin free phenytoin | 10–20 mcg/mL 1–2 mcg/mL | Trough: Immediately prior to dosing | 5–7 day after first dose or after change in dose |
Procainamide NAPA a procainamide metabolite | 4–10 mcg/mL Trough: 4 mcg/mL Peak: 8 mcg/mL 10–30 mcg/mL | Trough: Immediately prior to next dose or 12–18 h after starting or changing an infusion Draw with procainamide sample | |
Quinidine | 1–5 mcg/mL | Trough: Immediately prior to next dose | |
Sirolimus | 10–20 ng/dL | Trough: Immediately prior to next dose | |
Tacrolimus (FK-506) | 10–15 ng/mL | Trough: Immediately prior to next dose | Daily for first week, then weekly |
Theophylline p.o. or Aminophylline i.v. | 15–20 mcg/mL | Trough: Immediately prior to next dose | |
Valproic acid (divalproex sodium) | 40–100 mcg/mL | Trough: Immediately prior to next dose | Check 2–4 days after first dose or change in dose |
Vancomycin | Trough: 5–15 mg/L Peak: 25–40 mg/L | Trough: Immediately prior to dose Peak: 60 min after a 60 min infusion | With third dose (when initially starting therapy, or after each dosage adjustment). For therapy less than 72 h, levels not necessary. Repeat drug levels if renal function changes |
Table 20.5
Cyclosporine and tacrolimus drug–drug interactions
Drug | Mechanism | Effects | Severity | Comments |
|---|---|---|---|---|
Acetazolamide | Decrease clearance | Increase CSA/FK level | 3 | May cause acidosis |
Acyclovir | Crystallization in renal tubules | Nephrotoxicity | 4 | Avoid dehydration. Infuse over 1 h |
Amikacin | Synergistic nephrotoxicity | Nephrotoxicity | 3 | Monitor aminoglycoside level very closely. Target amikacin level peak 30–40 and trough less than 10 |
Amiloride | Decrease K+ secretion | Hyperkalemia | 3 | Avoid in transplant recipients |
Amiodarone | Decrease clearance | Nephrotoxicity | 3 | Very slow onset and offset |
Amlodipine | Decrease clearance | Increase CSA/FK level | 4 | 10–15 % increase in CSA/FK level |
Amphotericin B | Synergistic nephrotoxicity | Nephrotoxicity | 3 | Require hydration and electrolyte monitoring |
Atrovastatin | CSA decreases clearance of statins | Myopathy, rhabdomyolysis | 3 | Monitor CPK carefully |
Carbamazepine | Increase clearance | Decrease CSA/FK level | 3 | Slow onset (may take up to 7 days) Monitoring of CSA/FK level |
Carvedilol | Decrease clearance | Increase CSA/FK level | 3 | Can cause toxicity |
Cervastatin | CSA decreases clearance of statins | Myopathy, rhabdomyolysis | 3 | Require close CPK monitoring |
Chloroquine | Decrease clearance | Increase CSA/FK level | 3 | |
Cholestyramine | Increase clearance | Decrease CSA/FK level | 4 | Separate doses by 3 h |
Cimetidine | Inhibit creatinine secretion | Increase serum creatinine | 4 | Use other H2 antagonist agents (ranitidine, famotidine and nizatidine) |
Ciprofloxacin | Decrease CSA effects on IL-2 | Pharmacodynamic antagonism | 4 | May increase risk of rejection |
Cisapride | Decrease gastric emptying time | Increase CSA/FK level | 2 | Metoclopramide is the preferred agent |
Clarithromycin | Decrease clearance | Increase CSA/FK level | 2 | Azithromycin is the preferred agent |
Colchicine | Increase neurotoxicity | 3 | Gastrointestinal dysfunction and neuromyopathy | |
Co-trimoxazole | Inhibit creatinine secretion | Increase serum creatinine | 4 | Preferred agent for PCP |
Digoxin | CSA may decreases clearance of digoxin | Increase digoxin level | 3 | Monitor digoxin level closely |
Diltiazem | Decrease clearance | Increase CSA/FK level | 3 | Monitor CSA/FK level closely |
Enalapril | Renal dysfunction in RAS | Increase serum creatinine | 3 | May cause anemia. Use for treatment of post-transplant erythrocytosis |
Erythromycin | Decrease clearance | Increase CSA/FK level | 2 | Azithromycin is the preferred agent |
Fluconazole | Decrease clearance | Increase CSA/FK level | 3 | Increase LFTs, monitor levels carefully |
Fluvoxamine | Decrease clearance | Increase CSA/FK level | 2 | Monitor levels carefully |
Fosinopril | Renal dysfunction in RAS | Nephrotoxicity | 3 | Can cause elevation of Scr |
Fosphenytoin | Increase clearance | Decrease CSA/FK level | 3 | Monitor levels carefully |
Ganciclovir | Synergistic Nephrotoxicity | Nephrotoxicity | 3 | Avoid dehydration |
Gentamicin | Synergistic nephrotoxicity | Nephrotoxicity | 3 | Monitor blood concentrations very closely |
Griseofulvin | Unknown | Decrease CSA/FK level | 3 | Decreased cyclosporine effectiveness |
Itraconazole | Decrease clearance | Increase CSA/FK level | 3 | Monitor levels carefully, decrease dosage 50–85 % |
Ketoconazole | Decrease clearance | Increase CSA/FK level | 3 | Monitor levels carefully, decrease dosage 25–75 % |
Lovastatin | CSA decreases clearance of statins | Myopathy, rhabdomyolysis | 3 | Require close CPK monitoring |
Methy-prednisolone | Decrease clearance | Increase CSA/FK level | 3 | Only high doses |
Methytestosterone | Decreased cyclosporine metabolism | Increase CSA/FK level | 3 | Can cause toxicity |
Metoclopramide | Decrease gastric emptying time | Increase CSA/FK level | 3 | Increase peak and AUC by 25–50 % |
Metronidazole | Decrease clearance | Increase CSA/FK level | 4 | Monitor CSA/FK levels |
Mibefradil | Decrease CSA/FK clearance | Increase CSA/FK level | 3 | Monitor CSA/FK levels |
Nafcillin | Increase CSA/FK clearance | Decrease CSA/FK level | 3 | Monitor CSA/FK levels |
Nefazodone | Decrease CSA/FK clearance | Increase CSA/FK level | 3 | Monitor CSA/FK levels |
Nicardipine | Decrease CSA/FK clearance | Increase CSA/FK level | 3 | Monitor CSA/FK levels |
NSAIDs | Synergistic nephrotoxicity | Nephrotoxicity | 3 | CSA/FK induced vasoconstriction is influenced by prostaglandins inhibition |
Octreotide | Decrease intestinal absorption of CSA/FK | Decrease CSA/FK level | 3 | Monitor CSA/FK levels |
Phenobarbital | Increase CSA/FK clearance | Decrease CSA/FK level | 3 | Slow onset, slow off-set |
Phenytoin | Increase CSA/FK clearance | Decrease CSA/FK level | 3 | Monitor cyclosporine/FK levels |
Pravastatin | CSA decreases clearance of statins | Myopathy, rhabdomyolysis | 3 | Monitor CPK carefully |
Rifabutin | Increase CSA/FK clearance | Decrease CSA/FK level | 3 | Monitor CSA/FK levels, rifabutin is a less potent hepatic enzyme inducer than rifampin |
Rifampin | Increase CSA/FK clearance | Decrease CSA/FK level | 2 | Monitor cyclosporine/FK levels |
Sildenafil | Increase FK level | Decrease CSA/FK level | 4 | |
Simvastatin | CSA decreases clearance of statins | Myopathy, rhabdomyolysis | 4 | Monitor CPK carefully |
Spironolactone | Decrease K+ secretion | Hyperkalemia | 3 | Avoid |
Terbinafine | Decrease CSA/FK clearance | Increase CSA/FK level | 3 | Monitor CSA/FK levels |
Ticlopidine | Increase CSA/FK clearance | Decrease CSA/FK level | 3 | Monitor CSA/FK levels |
Tretinoin | Inhibit tretinoin metabolism | Increase tretinoin toxicity | 3 | |
Triamterine | Decrease K+ secretion | Hyperkalemia | 3 | Avoid |
Troglitazone | Increase CSA/FK clearance | Decrease CSA/FK level | 3 | Hepatotoxicity |
Valacyclovir | Hemolytic anemic syndrome | Renal dysfunction | 3 | Acyclovir or famciclovir are preferred agents for treatment of HSV and VZV |
Table 20.6
Sirolimus drug–drug interactions
Drug | Mechanism | Effects | Severity | Comments |
|---|---|---|---|---|
ACE-I | Synergestic myelosuppression | Anemia, neutropenia | 3 | Increase bone marrow toxicity |
Amprenavir | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 3 | Monitor sirolimus level |
Bromocriptine | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 3 | Monitor sirolimus level |
Carbamazepine | Decrease intestinal absorption | Decrease sirolimus level | 2 | Monitor sirolimus level |
Cholestyramine | Decrease intestinal absorption | Decrease sirolimus level | 3 | Monitor sirolimus level |
Clarithromycin | Increased plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level Azithromycin is the preferred agent |
Cyclosporine | Increase plasma level when taken at the same | Hyperlipidmia, anemia, neutropenia | 3 | Monitor sirolimus level, Give 4 h after the dose |
Danazol | Decrease intestinal absorption | Decrease sirolimus level | 3 | Monitor sirolimus level |
Diltiazem | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level Amlodipine is the preferred agent |
Erythromycin | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level Azithromycin is the preferred agent |
Fluconazole | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level |
Ganciclovir | Synergestic myelosuppression | Anemia, neutropenia | 3 | |
Indinavir | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level |
Itraconazole | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level |
Metoclopramide | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 3 | Monitor sirolimus level |
Nicardipine | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level Amlodipine is the preferred agent |
Phenobarbital | Increase metabolism | Decrease sirolimus level | 2 | Monitor sirolimus level |
Phenytoin | Increase metabolism | Decrease sirolimus level | 2 | Monitor sirolimus level |
Rifabutin | Increase metabolism | Decrease sirolimus level | 2 | Monitor sirolimus level |
Rifampin | Increase metabolism | Decrease sirolimus level | 2 | Monitor sirolimus level |
Ritonavir | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level |
TMP/SMX | Synergestic myelosuppression | Anemia, neutropenia | 3 | |
Verapamil | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level |
Voriconazole | Increase plasma level | Hyperlipidmia, anemia, neutropenia | 2 | Monitor sirolimus level |
Table 20.7
Azathioprine and mycophenolate drug–drug interactions
Drug | Mechanism | Effects | Severity | Comments |
|---|---|---|---|---|
ACE-I | Synergestic myelosuppression | Anemia, neutropenia | 3 | Increase bone marrow toxicity |
Acyclovir | Increase AUC of MMF | Not significant | 4 | |
Allopurinol | Inhibit xanthene oxidase | Severe neutropenia | 2 | Decrease azathioprine dose by 75 % |
Antacids | Decrease absorption of MMF | Decrease efficacy | 3 | |
Cholestyramine | Decrease absorption of MMF | 3 | Increase bone marrow toxicity | |
Ganciclovir | Synergistic myelosuppression | Anemia, neutropenia | 3 | |
TMP/SMX | Synergistic myelosuppression | Anemia, neutropenia | 3 |
Table 20.8
Dosage adjustment for immunosuppressive/modulators drugs
Immunosuppressant | Normal dosage | % of renal excretion | Dosage adjustment in renal failure | |||
|---|---|---|---|---|---|---|
GFR >50 mL/min | GFR 10–50 mL/min | GFR <10 mL/min | Comments | |||
Cyclosporine | 3 mg/kg/day | <5 | 100 % | 100 % | 50 % | Nephrotoxicity, HTN |
Tacrolimus | 0.1 mg/kg/day | <5 | 100 % | 75 % | 50 % | Nephrotoxicity, HTN |
Azathioprine | 2 mg/kg/day | <5 % | 100 % | 75 % | 50 % | Myleosuppression |
Mycophenolate | 1,000 mg bid | <1 % | 100 % | 100 % | 75 % | Myelosuppression |
Prednisone | Varies | <1 % | 100 % | 75 % | 25–50 % | Myelosuppression |
d-Penicillamine | 250–750 mg day | 5–15 % | 100 % | Avoid | Avoid | |
Hydroxychloroquine | 200 mg bid | 15–25 % | 100 % | 75 % | 50 % | Retinal toxicity or visual field |
Acitretin | 25–50 mg | <1 % | 100 % | Avoid | Avoid | |
Isotretinoin | 0.25–0.5 mg/kg q12 h | <1 % | 100 % | 100 % | 100 % | Avoid TCN, Vit A, and MTX |
Leflunomide | 10–20 mg daily | <1 % | 100 % | 100 % | 75 % | Liver toxicity, active metabolites eliminated through kidney |
MTX | 10–15 mg day | 70–80 % | 100 % | Avoid | Avoid | Myelosuppression |
Sulfasalazine | 1,000 mg BID–TID | 50 % | 100 % | 75 % | 50 % | Myelosuppression |
Etanercept | 50 mg every week | ND | 100 % | 100 % | 100 % | Infection |
Infliximab | 3 mg/kg every 8 weeks | <1 % | 100 % | 100 % | 100 % | Infection |
Adalimumab | 40 mg every other week | <1 % | 100 % | 100 % | 100 % | Infection |
Certolizumab | 400 mg every month | ND | 100 % | 100 % | 100 % | Infection |
Golimumab | 50 mg every month | ND | 100 % | 100 % | 100 % | Infection |
Rituximab | 1,000 mg every 2 weeks | <1 % | 100 % | 100 % | 100 % | Infection |
Abatacept | 500–1,000 mg every 2 weeks | <1 % | 100 % | 100 % | 100 % | Infection |
Tocilizumab | 4 mg/kg every 4 weeks | ND | 100 % | 100 % | 100 % | Infection |
Antimicrobal agents in renal failure | |||||||||
|---|---|---|---|---|---|---|---|---|---|
Dosage adjustment in renal failure | |||||||||
Drugs | Normal dosage | % of renal excretion | GFR >50 mL/min | GFR 10–50 mL/min | GFR <10 mL/min | Comments | HD | CAPD | Continuous venovenous hemofiltration |
Aminoglycoside antibiotics | Nephrotoxic, ototoxic Toxicity worse when hyperbilirubinemic Measure serum levels for efficacy and toxicity | ||||||||
Peritoneal absorption increases with presence of inflammation | |||||||||
Vd increases with edema, obesity, and ascites | |||||||||
Streptomycin | 7.5 mg/kg q12 h (1.0 g q24 h for TB) | 60 % | q24 h | q24 to 72 h | q72 to 96 h | For the treatment of TB. May be less nephrotoxic than other members of class | 1/2 normal dose after dialysis | 20–40 mg/L/day | Dose for GFR 10–50 mL/min and measure levels |
Kanamycin | 7.5 mg/kg q8 h | 50–90 % | 60–90 % q12 h or 100 % q12 to 24 h | 30–70 % q12 to 18 h or 100 % q24 to 48 h | 20–30 % q24 to 48 h or 100 % q48 to 72 h | Do not use once-daily dosing in patients with creatinine clearance less than 30–40 mL/min or in patients with acute renal failure or uncertain level of kidney function | 1/2 full dose after dialysis | 15–20 mg/L/day | Dose for GFR 10–50 mL/min and measure levels |
Gentamicin | 1.7 mg/kg q8 h | 95 % | 60–90 % q8 to 12 h or 100 % q12 to 24 h | 30–to 70 % q12 h or 100 % q24 to 48 h | 20–30 % q24 to 48 h or 100 % q48 to 72 h | 1/2 full dose after dialysis | 3–4 mg/L/day | Dose for GFR 10–50 mL/min and measure levels | |
Tobramicin | 1.7 mg/kg q8 h | 95 % | 60–90 % q8 to 12 h or 100 % q12 to 24 h | 30–70 % q12 h or 100 % q24 to 48 h | 20–30 % q24 to 48 h or 100 % q48 to 72 h | 1/2 full dose after dialysis | 3 to 4 mg/L/day | Dose for GFR 10–50 mL/min and measure levels | |
Netilmicin | 2 mg/kg q8 h | 95 % | 50–90 % q8 to 12 h or 100 % q12 to 24 h | 20–60 % q12 h or 100 % q24 to 48 h | 10–20 % q24 to 48 h or 100 % q48 to 72 | May be less ototoxic than other members of class. Peak 6 to 8 Trough <2 | 1/2 full dose after dialysis | 3–4 mg/L/day | Dose for GFR 10–50 mL/min and measure levels |
Amikacin | 7.5 mg/kg q12 h | 95 % | 60–90 % q12 h or 100 % q12 to 24 h | 30–to 70 % q12 to 18 h or 100 % q24 to 48 h | 20–30 % q24 to 48 h or 100 % q48 to 72 h | Monitor levels Peak 20 to 30 Trough <5 | 1/2 full dose after dialysis | 15–20 mg/L/day | Dose for GFR 10–50 mL/min and measure levels |
Cephalosporin | Coagulation abnormalities, transitory elevation of BUN, rash and serum sickness-like syndrome | ||||||||
Oral cephalosporin | |||||||||
Cefaclor | 250–500 mg q8 h | 70 % | 100 % | 100 % | 50 % | 250 mg bid after dialysis | 250 mg q8 to 12 h | N/A | |
Cefadroxil | 500 to 1 g q12 h | 80 % | 100 % | 100 % | 50 % | 0.5–1.0 g after dialysis | 0.5 g/day | N/A | |
Cefixime | 200–400 mg q12 h | 85 % | 100 % | 100 % | 50 % | 300 mg after dialysis | 200 mg/day | Not recommended | |
Cefpodoxime | 200 mg q12 h | 30 % | 100 % | 100 % | 100 % | 200 mg after dialysis | Dose for GFR <10 mL/min | N/A | |
Ceftibuten | 400 mg q24 h | 70 % | 100 % | 100 % | 50 % | 300 mg after dialysis | No data: Dose for GFR <10 mL/min | Dose for GFR 10–50 mL/min | |
Cefuroxime axetil | 250–500 mg q8 h | 90 % | 100 % | 100 % | 100 % | Malabsorbed in presence of H2 blockers. Absorbed better with food | Dose after dialysis | Dose for GFR <10 mL/min | N/A |
Cephalexin | 250–500 mg q8 h | 95 % | 100 % | 100 % | 100 % | Rare allergic interstitial nephritis. Absorbed well when given intraperitoneally. May cause bleeding from impaired prothrombin biosynthesis | Dose after dialysis | Dose for GFR <10 mL/min | N/A |
Cephradine | 250–500 mg q8 h | 100 % | 100 % | 100 % | 50 % | Dose after dialysis | Dose for GFR <10 mL/min | N/A | |
IV cephalosporin | |||||||||
Cefazolin | 1–2 g IV q8 h | 80 % | q8 h | q12 h | q12 to 24 h | 0.5–1.0 g after dialysis | 0.5 g q12 h | Dose for GFR 10–50 mL/min | |
Cefepime | 1–2 g IV q8 h | 85 % | q8 to 12 h | q12 h | q24 h | 1 g after dialysis | Dose for GFR <10 mL/min | Not recommended | |
Cefmetazole | 1–2 g IV q8 h | 85 % | q8 h | q12 h | q24 h | Dose after dialysis | Dose for GFR <10 mL/min | Dose for GFR 10–50 mL/min | |
Cefoperazone | 1–2 g IV q12 h | 20 % | No renal adjustment is required | Displaced from protein by bilirubin. Reduce dose by 50 % for jaundice. May prolong prothrombin time | 1 g after dialysis | None | None | ||
Cefotaxime | 1–2 g IV q6 to 8 h | 60 % | q8 h | q12 h | q12 to 24 h | 1 g after dialysis | 1 g/day | 1 g q12 h | |
Cefotetan | 1–2 g IV q12 h | 75 % | q12 h | q12 to 24 h | q24 h | 1 g after dialysis | 1 g/day | 750 mg q12 h | |
Cefoxitin | 1–2 g IV q6 h | 80 % | q6 h | q8 to 12 h | q12 h | May produce false increase in serum creatinine by interference with assay. | 1 g after dialysis | 1 g/day | Dose for GFR 10–50 mL/min |
Ceftazidime | 1–2 g IV q8 h | 70 % | q8 h | q12 h | q24 h | 1 g after dialysis | 0.5 g/day | Dose for GFR 10–50 mL/min | |
Ceftriaxone | 1–2 g IV q24 h | 50 % | No renal adjustment is required | Dose after dialysis | 750 mg q12 h | Dose for GFR 10–50 mL/min | |||
Cefuroxime sodium | 0.75–1.5 g IV q8 h | 90 % | q8 h | q8 to 12 h | q12 to 24 h | Dose after dialysis | Dose for GFR <10 mL/min | 1.0 g q12 h | |
Penicillin | Bleeding abnormalities, hypersensitivity. Seizures | ||||||||
Oral Penicillin | |||||||||
Amoxicillin | 500 mg po q8 h | 60 % | 100 % | 100 % | 50–75 % | Dose after dialysis | 250 mg q12 h | N/A | |
Ampicillin | 500 mg po q6 h | 60 % | 100 % | 100 % | 50–75 % | Dose after dialysis | 250 mg q12 h | Dose for GFR 10–50 mL/min | |
Dicloxacillin | 250–500 mg po q6 h | 50 % | 100 % | 100 % | 50–75 % | None | None | N/A | |
Penicillin V | 250–500 mg po q6 h | 70 % | 100 % | 100 % | 50–75 % | Dose after dialysis | Dose for GFR <10 mL/min | N/A | |
IV Penicillin | |||||||||
Ampicillin | 1–2 g IV q6 h | 60 % | q6 h | q8 h | q12 h | Dose after dialysis | 250 mg q12 h | Dose for GFR 10–50 mL/min | |
Nafcillin | 1–2 g IV q4 h | 35 % | No renal adjustment is required | None | None | Dose for GFR 10–50 mL/min | |||
Penicillin G | 2–3 million Units IV q4 h | 70 % | q4 to 6 h | q6 h | q8 h | Dose after dialysis | Dose for GFR <10 mL/min | Dose for GFR 10–50 mL/min | |
Piperacillin | 3–4 g IV q4 to 6 h | No renal adjustment is required | Sodium, 1.9 mEq/g | Dose after dialysis | Dose for GFR <10 mL/min | Dose for GFR 10–50 mL/min | |||
Ticarcillin/clavulanate | 3.1 g IV q4 to 6 h | 85 % | 1–2 g q4 h | 1–2 g q8 h | 1–2 g q12 h | Sodium, 5.2 mEq/g | 3.0 g after dialysis | Dose for GFR <10 mL/min | Dose for GFR 10–50 mL/min |
Piperacillin/tazobactam | 3.375 g IV q6 to 8 h | 75–90 % | q4 to 6 h | q6 to 8 h | q8 h | Sodium, 1.9 mEq/g | Dose after dialysis | Dose for GFR <10 mL/min | Dose for GFR 10–50 mL/min |
Quinolones | Food, dairy products, tube feeding, and Al(OH)3 may decrease the absorption of quinolones | ||||||||
Ciprofloxacin | 200–400 mg IV q24 h | 60 % | q12 h | q12 to 24 h | q24 h | Poorly absorbed with antacids, sucralfate, and phosphate binders. IV dose 1/3 of oral dose. Decreases phenytoin levels | 250 mg q12 h (200 mg if IV) | 250 mg q8 h (200 mg if IV) | 200 mg IV q12 h |
Levofloxacin | 500 mg po q24 h | 70 % | q12 h | 250 q12 h | 250 q12 h | L-isomer of ofloxacin: appears to have similar pharmacokinetics and toxicities | Dose for GFR <10 mL/min | Dose for GFR <10 mL/min | Dose for GFR 10–50 mL/min |
Moxifloxacin | 400 mg q24 h | 20 % | No renal adjustment is required | No data | No data | No data | |||
Nalidixic acid | 1.0 g q6 h | High | 100 % |
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