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Exam 2 Flashcards

1
Q

How are NRTIs affected by CYP 450 enzymes?

A

They are not

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2
Q

Which NRTIs have pre-dominantly non-renal clearance?

A

ABC and ZDV

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3
Q

How are most NRTIs eliminated?

A

Renal

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4
Q

What is the half-life of the triphosphates?

A

Variable

3-40 hours

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5
Q

How are EFV/NVP/RVP affected by CYP 450 enzymes?

A

Substrates, inhibitors, and inducers of 3A4

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6
Q

What are ETV affected by CYP 450 enzymes?

A

Substrate for 3A4, 2C9, and 2C19
Inducer of 3A4
Inhibitor of 2C9 and 2C19

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7
Q

How are PIs affected by CY{ 450 enzymes?

A

Extensive metabolism - substrates, inhibitors and inducers

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8
Q

How are PIs affected by P-gp enzymes?

A

Substrates and inhibitors

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9
Q

How is ritonavir affected by P-gp enzymes?

A

Inhibitor

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10
Q

How is enfuviritide affected by enzymes?

A

Enfuviritide is a peptide and gets broken down enzymatically to aa’s that are then recycled into the body pool

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11
Q

How is Maravaroc affected by CYP 450 enzymes?

A

3A4 substrate

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12
Q

What enzymes affect INSTIs

A

RAL: glucuronidated by UGT 1A1
EVG: CYP 450 substrate
DTG: mainly glucuronidated, some 3A4

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13
Q

How are PK enhancers affected by enzymes?

A

Inhibitors of:
3A4 and 2A6
P-gp, BCRP, OATP1A1, OATP1B3

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14
Q

What is the PK result of EFV/NVP + rifampin and how do you change the dose?

A

Decreased [EFV/NVP]

Increase EFV

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15
Q

What is the PK result of EFV/NVP + statins and what do you do?

A

Decreased [statin]

Monitor cholesterol closely/more aggressive statin dose

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16
Q

What is the PK result of RPV + PPIs and what do you do?

A

Decreased RPV

Avoid PPIs w/RPV

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17
Q

What is the PK result of ETV + certain boosted PIs (ATV/r, FPV/r, TPV,r)

A

Decreased [PI]

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18
Q

What is the PK result of ETV + warfarin and what do you do?

A

Increased [warfarin]

Monitor INR

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19
Q

What is the PK result of PIs + rifampin?

A

Decreased [PI]

Increased [RIF]

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20
Q

What are the 6 contraindicated drugs with PIs?

A 
RIF
Midazolam/triazolam
Ergot derivatives
St. John's Wort
Lovastatin/simvastatin
Pimozide
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21
Q

What is the PK result of PIs + midazolam/triazolam?

A

Increased [midaz/triaz]

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22
Q

What are the PK results of PIs + ergot derivatives?

A

Increased [ergots]

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23
Q

What are the PK results of Pis + St. John’s Wort?

A

Decreased [PI]

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24
Q

What are the PK results of PIs + lovastatin/simvastatin?

A

Increased [Lovastatin/simvastatin]

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25
What are the PK results of PIs + pimozide?
Increased [pimozide]
26
What are the PK results of ATV + PPIs and what do you do?
Decreased [ATV] Max omeprazole 20mg/d equivalent Aalways boost w/RTV Avoid in experienced pts with resistance
27
What are the PK results of Pis + amiodarone, lidocaine, ruinide, bepridil and what do you do?
Increased [anti-arrhythmics] Avoid if possible TDM
28
What are the PK results of PIs + trazodone and what do you do?
Increased [trazodone] | Use lowest dose possible
29
What are the PK results of PIs + immunosuppressants and what do you do?
Increased [immuno.] | TDM
30
What are the PK results of PIs + statins and what do you do?
Increased [statins] | Prava/atorv preferred (+/- rosuv)
31
What are the PK results with fusion inhibitor interactions?
There are none
32
What are the PK results of MVC + inducers and what do you do?
Decreased [MVC] | Double MVC dose
33
What are the PK results of MVC + inhibitors and what do you do?
Increased [MVC] | 1/2 MVC dose
34
What are the PK results of RAL + rifampin and what do we do?
Decreased [RAL] | Double RAL dose
35
What are the PK results of RAL + pheny/phenobarb and what do we do?
Potential decreased [RAL] | Use with caution
36
What are the PK results of elvitegravir with interacting drugs?
Similar interactions with ritonavir | See PIs/cobi
37
What are the PK results of DTG + dofetilide and what do you do?
Increased [dofetilide] | CONTRAINDICATED
38
What are the PK results of DTG + rifampin and what do you do?
Decreased [DTG] | Increase DTG dose
39
What are the PK results of DTG + cations and what do you do?
Decreased [DTG] | Take DTG 2h before/6h after cations
40
Which drugs are contraindicated for use with PK enhancers?
``` COBI + rifampin COBI + ergot derivatives COMI + St. John's Wort COBI + lova/simva COBI + sildenafil for PAH COBI + PO triaz/midaz ```
41
What are the PK results of COBI + sildenafil for PAH?
Increased [sildenafil]
42
What is the most common type of PD?
CAPD: Continuous ambulatory peritoneal dialysis
43
What GFR rate do patients receiving peritoneal dialysis act like?
10-20 ml/min
44
How is PD added to a patient?
Invovles surgical insertion of a catheter in the lower abdomen in to the peritoneal cavity
45
Is HD or PD more efficient?
HD is more efficient
46
What is a common infxn in PD?
Peritonitis
47
What is the most common continuous renal replacement?
CVVH
48
Which dialysis is considered "low-flux"?
HD
49
Which dialysis removes larger molecules?
Continuous renal replacement
50
In continuous renal replacement, is the fraction of drug removed bound or unbound?
Unbound
51
How does the patient's GFR behave in continuous renal replacement?
~30 ml/min
52
How does HD work?
Blood is pumped out of the patient, cleaned, then returned
53
How does MW affect dialysis?
"Low-flux" have relatively small p[ores. | Small drug molecules (< 500 daltons) tend to be eliminated by dialysis.
54
How does water/lipid solubility affect dialysis?
Drugs that have a high degree of water solubility tend to partition into water-based dialysis fluids, whereas lipid-soluble drugs tend to remain in the blood
55
How does plasma protein binding affect dialysis?
Only unbound drug molecules are able to pass through the pores. Drugs that are not highly plasma protein-bound have high free fractions of drug in the blood and are prone to better dialysis clearance
56
How does Vd affect dialysis?
Medication with large Vd's are principally located at tissue binding sites and not in the blood, where dialysis can remove the drug. < 1 L/kg more likely to be removed (AGs, theophylline)
57
How does inherent clearance (route and rate) affect dialysis?
If kedney is the primary route of elimination - higher likelihood that drug will be removed by dialysis
58
What are the critically dosed agents?
CsA TAC SIR Everolimus
59
What are the critically-dosed NTI ratios?
< 2 fold difference b/n LD50 and ED50 OR < 2 fold difference in min. toxic conc. and min. effective conc. AND Safe and effective use requires careful titration and patient monitoring
60
What are the goals of critically-dosed agents?
Optimize drug therapy for individual patients Minimize risk of allograft rejection Minimize risk of dose-related adverse events Optimize immunosuppressive therapy
61
What is the indication for critically dosed immunosuppressants?
Prevention of allograft rejection
62
What is the Tmax for CsA?
2-4 hours
63
What is F for CsA?
5-70%; average 30%
64
What is Vd for Csa?
3-7 L/kg
65
What percent of CsA is bound to erythrocytes in blood?
70% | Preferred sampling matrix
66
What is CsA bound to in plasma?
Associated with lipoproteins
67
What is the metabolism of CsA?
By hepatic and intestinal 3A4 and transport by P-gp
68
What are variables that modulate CsA oral bioavailability?
intestinal P-gp and 3A4 activity
69
Is CsA renally eliminated?
Minimally
70
What is the half-life of CsA?
12-16 hours
71
What is F for TAC IR?
5-67%, average 27%
72
What is Tmax for TAC IR?
2-4 hours
73
What is F for TAC XR?
~50% higher than with immediate formulation (healthy subjects) F is better on an empty stomach and in the morning hours
74
What is F for TAC XL?
Better on an empty stomach and in the morning hours
75
What is Tmax for TAC XR?
6-8 hours
76
What is Tmax for TAC XL?
2-4 hours
77
What is Vd for TAC?
5-6 L/kg
78
How is TAC bound in the blood?
70-80% erythrocytes
79
How is TAC bound in plasma?
88% albumin and alpha-1 acid glycoprotein
80
How is TAC metabolized?
Hepatic and intestinal 3A4 and transported by P-gp
81
How is TAC eliminated?
Minimal renal elimination (< 5%)
82
What is the half-life of TAC IR?
3.5-40.5 hours, average 12 hours
83
What is the half-life of TAC XR?
31 +/- 8 hours
84
What is the half-life of TAC XL?
38 +/- 3 hours
85
What is F for SIR?
15% | Poorly absorbed
86
What is Tmax for SIR?
1.42 +/- 1.2 hours
87
What is Vd for SIR?
14 L/kg (range 4-20)
88
How is SIR bound in blood?
95% RBCs
89
How is SIR bound in plasma?
40% lipoproteins
90
How is SIR metabolized?
3A4 and transported by P-gp
91
How is SIR eliminated?
< 2.2% renally
92
What is the half-life of SIR?
57-63 hours (need LD and MD)
93
What is F for Everolimus?
30% (reduced with meals)
94
What is Tmax for Everolimus?
1-2 hours
95
What is the Vd for Everlimus?
2-5 L/kg
96
How is Everolimus bound in the body?
~70% plasma protein
97
How is Everolimus metabolized?
Substrate for 3A4 and P-gp
98
How is Everolimus eliminated?
Feces (80%) | Minimal renal elimination (5%)
99
What is the half-life for Everolimus?
30 hours
100
What is the standard of care at most hospital for CsA?
Pre-dose trough whole blood concentrations
101
What is the new option for CsA administration?
Single point sampling 2 hours after drug administration
102
Which weight do we use for CsA?
ABW
103
What is the dosing for CsA?
Initial 2.5 mg/kg PO q12h, then titrated based on SS trough blood levels
104
How often do we monitor CsA levels?
3x/wk for 1st month, then 2x/wk for the next 2 months, then weekly for 3 months, then monthly thereafter or after any dose change
105
How do we adjust CsA doses?
25-50mg PO q12 to achieve therapeutic levels
106
What is the PO:IV conversion of TAC?
3:1 PO:IV
107
What is monitored for TAC dosing?
High correlation between trough, Cmax, and AUC0-4. | Pre-dose trough whole blood concentration is the standard of care.
108
What is TAC IR dosing?
0.075 mg/kg PO q12 then titrated based on SS trough blood levels
109
What is TAC XR dosing
Conversion from IR to XR: 80% of the daily dose
110
What is TAC XL dosing?
Conversion from IR to XL: 1:1
111
When do we monitor SS levels?
2-3x/wk for the 1st month, then 2x/wk for the next 2 months, then weekly for 3 months, then monthly thereafter or after any dose change
112
How are TAC doses adjusted?
IR: Adjust doses by 1-2mg PO q12 to achieve therapeutic levels XR/XL: no clear guidance; take into account that it takes 7 days to acheive SS
113
How is SRL monitored?
High correlation between SS and AUC | Whole blood trough monitoring is standard of care
114
How do we calculate LD for SRL?
LD should be 3x MD
115
What is SRL dosing for low-moderate immunologic risk?
6mg LD, followed by 2mg daily
116
What is SRL dosing for high-immunologic risk?
15mg LD, followed by 5mg daily
117
How do we monitor SRL?
Very long half-life Adjusting doses before SS is reached can lead to over- or under-dosing Weekly for the 1st month post-transplant then monthly/every 3 months thereafter or after any dosing change
118
How do we adjust SRL dosing?
By 1-2 mg/d
119
What are the strategies for Everolimus monitoring?
High correlation between trough, Cmax and AUC 0-4 | Pre-dose trough whole blood concentration is the standard of care
120
How do we dose Everolimus in liver transportation, rejection prophylaxis?
1mg BID, then titrate as needed at a 4-5 day interval
121
How do we dose Everolimus in kidney transplantation, rejection prophylaxis?
0.75mg BID, then titrate as needed at a 4-5 day interval
122
What is the therapeutic range for Everolimus?
3-5 ng/ml, when given in conjunction with a calcineurin inhibitor
123
How do we monitor SS levels?
1-2x/wk for the 1st month, then as clinically indicated
124
How do we adjust Everolimus doses?
0.25-0.5mg PO q12 to achieve therapeutic levels
125
What are some 3A4/P-gp inhibitors?
Macrolides (except zithro) Non-dihydropyridine CCBs Azole antifungals PIs, cobi
126
What are some 3A4/P-gp inducers?
Phenytoin Phenobarbital Rifampin, Rifabutin Carbamazepine
127
How do statins interact with immunosuppressants?
3A4 substrate CsA is a substrate and inhibitor of 3A4 TAC/SRL substrates and weak inhibitors of 3A4 Potential to increase statin concentrations with concomitant use
128
How does grapefruit juice affect immunosuppressants?
``` Inhibit P-gp and 3A4 in the gut Increased Cmax and AUC No change in CL or half-life Increased C0 concentrations by 77% Increased CSA/TAC/SRL/EVR drug concentrations ```
129
How does St. John's Wort affect immunosuppressants?
Induce intestinal/hepatic 3A4 Induce P-gp in gut (decreased drug absorption = decreased bioavailability) Decreased CSA/TAC/SRL/EVR drug concentrations
130
Which drugs increase the risk of nephrotoxicities when taken with immunosuppressants?
AG Ampho. B Vanc NSAIDs
131
How often do we monitor CSA/TAC trough levels?
2-3 days after drug initiation and adjust dose appropriately
132
How do we monitor ARL trough levels?
1 week after drug initiation and adjust dose accordingly
133
How do we monitor EVR trough levels?
4-5 days after drug initiation and adjust dose
134
What is Harvoni's Tmax?
4 hours
135
Which drugs are in Harvoni?
SOF and LDV
136
What is SOF?
NS5B nucleotide polymerase inhibitor
137
What is LDV?
NS5A inhibitor
138
How is SOF distributed?
65% bound to human plasma protein
139
How is LDV distributed?
> 99% bound to plasma proteins
140
How is SOF metabolized?
Hydrolysis and phosphorylation to an active metabolite
141
How is LDV metabolized?
Via oxidative metabolism
142
How is SOF cleared?
Renally (80%)
143
What is the half-life of SOF?
25 hours
144
How is LDV eliminated?
Biliary/feces
145
What is the half-life of LDV?
47 hours
146
What drugs are in epclusa?
SOF and VEL
147
What is VEL?
NS5A inhibitor
148
What is Tmax of Epclusa?
3 hours
149
How is VEL distributed?
> 99% bound to plasma proteins
150
How is VEL metabolized?
2B6, 2C8, 3A4
151
How is VEL eliminated?
Biliary/feces
152
What is the half-life of VEL?
15
153
What drugs are in Viekira XR?
Omb, Pari, Ritonavir, Das
154
What is Omb?
NS5A inhibitor
155
What is pari?
NS3/4A protease inhibitor
156
What is ritonavir?
PK enhancer
157
What is Das?
NS5B
158
What is the Tmax of Viekira XR?
4-8 hours | Should be taken with food
159
How is Viekira XR distributed?
Highly bound to human plasma proteins
160
What is Vd of Viekira XR?
High apparent Vd (V/F) for all 4 components
161
How is Omb metabolized?
Amide hydrolysis, followed by oxidative metabolism
162
How is Pari metabolized?
3A4 (major)
163
How is ritonavir metabolized?
Mostly 3A4 | To a lesser extent 2D6
164
How is Das metabolized?
Mostly 2C8 | To a lesser extent 3A4
165
How is Viekira XR eliminated?
Predominantly feces | Minimal renal elimination
166
What is the half-life of Omb?
21-25 hours
167
What is the half-life of Pari?
5.5 hours
168
What is the half-life of ritonavir?
4 hours
169
What is the half-life of Das?
5.5-6 hours
170
What drugs are in Zepatier?
Elb and Graz
171
What is Elb?
NS5A inhibitor
172
What is Graz?
NS3/4A protease inhibitor
173
What is the Tmax of Elb?
3-6 hours
174
What is the Tmax of Graz?
0.5-3 hours
175
How is Zepatier distributed?
> 97% bound to plasma proteins | High Vd
176
How is Zepatier metabolized?
Primarily 3A4
177
What is the only DAA that is approved for patients with all CrCl?
Zepatier
178
How is Zepatier eliminated?
Predominantly via feces | Minimal renal elimination
179
What is the half-life of Elb?
24 hours
180
What is the half-life of Graz?
31 hours
181
What drugs are not recommended to be taken with Harvoni or Epclusa?
Amiodarone P-gp inducers: rifampin, St. John's Wort Anticonvulsants
182
What drugs are contraindicated with Viekira XR?
Anticonvulsants: carbamazepine, phenytoin, phenobarbital
183
How does ritonavir affect 3A4
Inhibitor of 3A4
184
What drugs are contraindicated with Zepatier?
Anticonvulsants: Phenytoin, carbamazepine Antimycobacterial: rifampin Herbal: St. John's Wort HIV meds: CsA
185
What drugs are not recommended with Zepatier?
3A4 inducers: nafcillin | 3A4 inhibitors: ketoconazole, cobi
186
What is a post-antibiotic effect?
Continued suppression of bacterial growth after a short exposure to antimicrobial agents
187
What is a time-dependent ABX?
Amount of microbial killing depends on the time the drugs stays above the MIC T > MIC
188
What is a concentration-dependent ABX?
Amount of microbial killing depends on the max concentration of drug above the MIC
189
What is the goal of therapy for time-dependent an minimal PAE abx when T > MIC?
Maximize duration of exposure
190
What is the goal of therapy for time dependent and minimal PAE of abx when 24h-AUC/MIC
Maximize amount of drug
191
What is an example of ABX for time-dependent and minimal PAE with T > MIC?
PCN
192
What is an example of ABX for time-dependent and minimal PAE with 24h-AUC/MIC?
Vancomycin
193
What is an example of ABX for time-dependent and moderate to prolonged PAE?
Azithromycin
194
What is the goal of therapy for time dependent and moderate to prolonged PAE?
Maximize amount of drug
195
What is an example of concentration-dependeMICnt and prolonged PAE?
FQs
196
What is the goal of therapy for concentration-dependent and prolonged PAE?
Maximize concentrtaion
197
What is fT > MIC?
Amount of time the free or non-protein bound drug concentrations exceeds the
198
What are the advantages for using extended infusions of ABX?
Superior PD profile (more fT > MIC) Allows for time between doses for administrations of drugs through the same IV line Cost saving
199
What is the rationale for using ABX drug combinations?
``` Broad-spectrum empiric therapy Polymicrobial infections Decrease resistance Decrease dose-related toxicity Increase inhibition or killing ```
200
What are some examples of antagonism?
Vanc + linezolid | Two beta-lactams
201
What mechanism does Bactrim work?
Blockade of sequential steps in a metabolic sequence
202
What mechanism do beta-lactam/B-lactamse combos work?
Inhibition of enzymatic inactivation
203
What mechanism do PCN G and gent work by?
Enhancement of abx uptake
204
By what mechanism does vanc + linezolid inhibit each other?
Inhibition of cidal activity by static agents
205
By what mechanism does two beta-lactams inhibit each other?
Induction of enzymatic inactivation

PK (6 decks)

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